Sarepta Therapeutics, Inc. (SRPT) Earnings Call Transcript & Summary

Good morning, ladies and gentlemen, and welcome to the Sarepta Therapeutics Clinical Updates: Gene Therapy Programs Presentation. [Operator Instructions] As a reminder, today's program is being recorded. And now I'll turn the call over to Doug Ingram, President and CEO, for opening remarks. Please go ahead.

Good morning, everybody, and thank you for joining us this morning as we provide some clinical updates for our 2 most advanced gene therapy programs, SRP-9001 and SRP-9003. This is Doug Ingram. I am the CEO of Sarepta. I am going to turn over the call momentarily to Dr. Louise Rodino-Klapac, who will go through updates on both of those programs. Before I do, I would remind you that we will very likely, either in the main presentation or in the Q&A, make some forward-looking statements or, in other words, some potential statements about future events. One should review our public filings for a full list of the risks that are attendant whenever one attempts to make statements about the future. And with that, let me turn the call over to Dr. Rodino-Klapac. Louise?

Thank you, Doug. I'm very pleased to be giving an update on our 9001 program for Duchenne muscular dystrophy, this is our 2-year functional data, as well as our 18-month functional data for our LGMD2E program or SRP-9003. First, starting out in consideration for development of gene transfer therapy, durability is a key consideration. And so we'd like to take a moment to discuss the durability of transgenes delivered via AAV vectors to date, and this spans across multiple programs in gene therapy. Speaking first in terms of the data to date in hemophilia in both nonclinical models and human models. There's data up to 8 years in canine models, up to 10 years in humans in 1 trial and 3 years in another trial. And this is important in terms of collective data for the durability of gene transfer. Additional data in other programs like SMA, including nonclinical models for the lifespan of the mouse, 250 days, or 5 years using AAV9. With respect to our limb-girdle and Duchenne programs, which we'll talk about, in limb-girdle, we also have data showing durability for the lifespan of the mouse 24 months and in the human for 18 months. Finally, in our Duchenne program, we have data in humans, 2 years, which we'll talk about today. There's also additional data in the canine model for 8 years. So let's go into a little bit more detail about durability. Muscle is really an ideal tissue for durability of gene transfer. And there are several reasons why this is. One, skeletal muscle is post mitotic, meaning it no longer divides in adult muscle, so after birth, under normal conditions, there's only very sporadic incorporation of what's called satellite cells or muscle stem cells to compensate for daily wear and tear. There's specific data in muscles called the intercostal muscles, which support the ribs that show an average muscle cell lives for about 15 years in adults. In cardiac muscle, there's even less turnover, with less than 50% of cardiomyocytes exchange over the normal life span, and this turnover decreases exponentially with age to less than 1% in adults. Now durability is affected by multiple factors for gene therapy. One is the viral vector transduction and biodistribution. The selection of the AAV serotype, for example. We've selected rh74, which distributes to both skeletal muscle, cardiac muscle, diaphragm muscle very well in a robust manner. Also the choice of promoter, how much expression you're getting and also in terms of corticosteroid use. And so the point being is that the more robust expression that you can achieve in terms of widespread transduction as well as levels, that can influence the durability of gene transfer over time. Again, just emphasizing that in the BMD model, we have seen durability for up to 8 years and continuing on as well. So now turning to our Duchenne muscular dystrophy program, SRP-9001. We will be giving a clinical update on our first study. This is an open-label study in 4 patients with Duchenne muscular dystrophy. I'll just remind you quickly that Duchenne is a rare fatal neuromuscular disease. It's inherited in an X-linked recessive pattern that affects male newborns. Muscle weakness is noticeable by age 3 to 5 but most patients are dependent on a wheelchair by the time they are 11. The disease is severe with cardiac and respiratory symptoms leading to significant serious life-threatening complications, ultimately leading to death. Our open-label trial design, we have 4 patients between the ages of 4 to 7 years of age with confirmed DMD mutations. The individuals also have to be negative for antibodies to AAVrh74. In terms of endpoints, this is an open-label safety study as the primary endpoint but with several key secondary endpoints, which included micro-dystrophin expression, decrease in creatine kinase, the 100-meter timed test, North Star Ambulatory Assessment, which includes the 10-meter timed test and multiple other timed tests, including timed up and go, ascending stairs and also cardiac MRI. These are patient demographics at baseline. They range from 4 to 6 years of age at the age of treatment, and their CK levels were significantly elevated as you would expect in Duchenne patients by this age, ranging from about 20,000 to about 35,000. Now there are several questions to consider when evaluating gene transfer therapy. And I'd like you to keep that in mind as we go through this talk, and we'll keep reminding you of that. So first and foremost, was the treatment safe and was it tolerable? Next, how efficient was the gene transfer, and we can measure this by measuring the amount of vector genome copies per nucleus. And does this transduction lead to protein production? We measure the total amount of protein production by Western blot, followed by localization. So was that correctly localizing at the membrane in the case of micro-dystrophin? And then we measure that in terms of number of fibers and the intensity of those fibers at the membrane. And does this membrane staining lead to reconstitution of the dystrophin-associated protein complex, which then leads to function, including the NSAA and timed function tests, which we'll go through in detail? Turning first to safety. I'll remind you, we now have 2-year safety data in these first 4 patients. There were no SAEs or any AEs that led to a discontinuation. There were no abnormalities in hematologic or chemistry panels, which included liver function tests. No serious AE. Three patients had elevated gamma GT in the first 3 months post treatment, and that resolved quickly with steroid treatment. There were no other clinically significant laboratory findings reported, including that platelets remained in the normal range. The most common treatment-related adverse event was vomiting, which consisted of 9 of the 18 treatment-related adverse events. Patients had transient vomiting generally within the first week post infusion, which did not correlate with liver enzyme elevations or any other abnormality. And all of these occurred within the first 90 days. None of the adverse events were associated with complement activation. So now turning to the biopsy. We took muscle biopsies at baseline and at 12 weeks post gene transfer. We saw a mean of 3.3 copies per nucleus in these first 4 boys. And this is translating into meaningful and robust levels of micro-dystrophin expression. Looking at a mean across all 4 patients, we see 74.3% as compared to normal when not adjusted for fat and fibrosis. When you do adjust for fat and fibrosis, we see 95.8% expression compared to normal by Western blot. Next, we look at micro-dystrophin expression at the membrane. And again, we quantified this by counting the number of fibers positive for micro-dystrophin, which we see a mean of 81.2%, and then also quantified the intensity as compared to normal. And here, we see 96% intensity. Next, we looked for restoration of dystrophin-associated protein complex. And one of the key members of this complex is beta-sarcoglycan. As you can see pretreatment, we see very low levels of beta-sarcoglycan, which post treatment is significantly restored to the membrane and correctly localized to the muscle cell membrane in all 4 patients. We also looked at histology of the muscle and quantified the amount of fibrosis in the muscle biopsy. This is a staining called sirius red, which stains for collagen, as you can see here in pink. So the healthy muscle fibers are in the bluish green color and fibrosis is in pink. And what you can see is that we see a significant reduction in the collagen content or the fibrosis content post gene therapy for 12 weeks. Now I'll turn to this functional data. Now previously, we've shared our 1-year functional data, and now we're updating to 2 years. First, this is the North Star Ambulatory Assessment. This is an aggregate of 17 measures for a total of 34 points. And what you can see is that at 2 years, we are still seeing sustained or improvement in function in the NSAA over that time point. So we see a mean change of 7 points from baseline to 2 years across our 4 patients. At year 1, you can see we had a 5.5 point increase. And at year 2, we now see a 7 point increase across these 4 patients. Looking at a summary of the timed function test. What you can appreciate is that we see a sustained or improved function across our 4 patients in all these tests as well. So I'll remind you for the timed function test, including time to rise, 4-stair climb, 100-meter, we're looking for a reduction in the amount of time it takes to do that activity. And looking across, you can see improvements in our patients or sustained benefits. I'll just have you focused on the 100-meter percent predicted. This is a way of measuring the percent function as compared to a normal age-matched individual. And what you can see in all 4 patients is that we've seen improvement in the percent predicted value for 100-meter in our 4 patients. So just to summarize the results from our 101 2-year study. In terms of safety, we saw 3 subjects at elevated gamma GT and that quickly resolved. We had transient vomiting, which did not correlate with enzyme elevation, normal platelet counts and no other clinically significant laboratory findings. In terms of our muscle biopsies, we saw a mean of 3.3 vector copies per nucleus. Our Western blot, 74.3% or 95.8% expression compared to normal if you adjust for fat and fibrosis. 81.2% dystrophin-positive fibers with 96% intensity. And in terms of function, we saw a mean 7 point improvement on NSAA from baseline to year 2. So now turning to our limb-girdle muscular dystrophy type 2E program, or 9003. This is a Phase I/II study, open-label study in 6 patients. Just to orient you on limb-girdle muscular dystrophy, the LGMDs as a whole have a global prevalence of 1.63 per 100,000. There are over 30 subtypes of LGMD with both genders affected. The LGMDs are genetically heterogeneous. But when you're looking at individual subtypes, you see more uniform distribution. In LGMD, the muscle weakness begins in the hips and shoulder girdle, as you can see by the image, but then the weakness does eventually expand distally and can also involve the cardiac muscle as is the case in LGMD2E as well as the diaphragm. So just to summarize our preclinical findings to date here, in terms of safety, we've seen a low prevalence of pre-existing antibodies. As far as vector distribution to muscle in preclinical models, we see greater than 10^5 copies in all muscles, including the heart and diaphragm that we've looked at. Expression is greater than 90% in both skeletal muscle and the heart. And we see beta-sarcoglycan correctly localized at sarcolemma by immunofluorescence and restoration of the other DAPC proteins, and it's translated into significant improvements in specific force, fatigue, kyphoscoliosis and activity and movement in the preclinical animal models for LGMD2E. Just to show you some of this data, this is our durability data in the LGMD2E knockout mouse model. And what you can appreciate here is that the animals completed early, and then we shared expression as of 6 months, also out to 28 months. And you can see that there was no diminishment of expression over that time frame. It was greater than 90% of fibrosis across every single muscle group, including the heart and diaphragm. And on the right, this is just a representative image of expression of both skeletal muscle and in the heart at 27 months. The SRP-9003 study is an open-label trial design with key inclusion criteria of confirmed beta-sarcoglycan mutations in both alleles. Patients have to be negative for rh74 antibodies and be greater than 40% of normal on a 100-meter walk test. Prednisone at 1 mg per kg was started daily 1 day before study treatment for 30 days in cohort 1 and 60 days in cohort 2 before beginning taper. Muscle biopsies were taken at baseline and 60 days. Primary endpoint is safety with secondary endpoints being beta-sarcoglycan expression at week 8. Other secondary endpoints included change in CK and functional endpoints, which included the North Star Ambulatory Assessment, 100-meter walk, 10-meter walk, 4-stair climb and time to rise. These are the subject demographics at baseline. In terms of gender distribution, we've seen an equal number of males and females across our 2 cohorts. Ages ranged from 4 to 13 years of age. All of the mutations were severe. 5 of 6 patients had mutations in exon 3 or 4. Mutations in these exons lead to complete absence or severely reduced expression of beta-sarcoglycan, and that includes cardiomyopathy. Our sixth patient had a mutation in the very first proton of exon 1 leading also to complete absence of protein. We had a wide weight range between 17 and 57 kilograms. And so this really gave us important safety experience across the large weight range for our program for muscular dystrophy. We also saw elevated creatine kinase levels in both cohorts as well. There were 2 dosing levels. In cohort 1 the dose is 5x10^13 vector genomes per kilogram, otherwise stated as 0.5x10^14 vector genomes per kilogram. Cohort 2, we saw a fourfold increase for a dose of 2x10^14 vector genomes per kilogram. Again, in terms of what to consider when evaluating gene transfer therapies, we'll go through the same paradigm. We'll be first looking at safety, then in muscle biopsies looking at transduction viral vector copies, Western blot for total expression, immunofluorescence for localization of that expression and functional outcomes, which include NSAD and timed function tests. First, focusing on safety. This will first focus on cohort 1. In this cohort, 2 subjects had elevated liver enzyme. One was designated as an SAE as the subject had associated transient increase in bilirubin. One event occurred when the subject was tapered off of oral steroids and the other while the patient was being tapered. These both returned to baseline very quickly and the symptoms resolved within days following supplemental steroid treatment. One patient experienced mild vomiting, which resolved within 1 day without treatment, and there were no other clinically significant laboratory findings or no decreases in platelet counts out of the normal range and no clinical sequelae associated with complement activation. In cohort 2, the majority of AEs were mild to moderate and resolved easily. There was one treatment-related SAE observed, and this was dehydration resulting from vomiting 3 days after infusion. This resolved quickly within 2 days with antiemetics and IV fluids. We had one patient with mildly elevated GGT, which returned to normal limits while on tapering dose of steroids. And the patient did not experience an increase after tapering was concluded. If you remember, for our cohort 2, we increased the steroids for 60 days prior to tapering for this cohort. There were no stopping or discontinuation rules triggered by AEs and no other clinically significant laboratory findings, including no decreases in platelets or complement activation. Now turning to our biopsy data. Again, we had biopsies at baseline and at 60 days. In our first cohort, we saw a mean of 0.6 copies per nucleus at low dose. And at the high dose with a fourfold increase, we see a mean of 4.2 copies per nucleus. Now turning to expression. By Western blot, for cohort 1, we had a mean of 36.1% as compared to normal. And as expected in our high-dose cohort, we saw a mean of 62.1% compared to normal. So we saw an almost doubling of expression by Western blot in our second cohort. In terms of percentage of positive fibers and intensity in our low-dose cohort 1, we see 51% of muscle fibers expressing beta-sarcoglycan with an intensity of 47% as compared to normal. In our high-dose cohort, we saw that increase to 72% beta-sarcoglycan positive fibers with an intensity of 73%. This led to an expected reconstitution of the dystrophin-associated protein complex. So what we're showing here is staining for beta-sarcoglycan in green and alpha-sarcoglycan at the same time. And what you can see in the colocalization image is that these are localizing together at the membrane in the appropriate place. We also looked at creatine kinase levels and what we're showing here is both cohort 1 and cohort 2. And what we can see at day 90, we see a dramatic decrease -- increase in kinase levels, which was 83.4% for cohort 1 and 89.1% for cohort 2. Now I'll turn to our functional data. And so what we'll be sharing here is our 18-month functional data for cohort 1 and an early read, our 6-month functional data for our high-dose cohort, cohort 2. So what we're showing here is a summary data for cohort 1 for the NSAD over 18 months. And what you can appreciate is that we see a sustained improvement in the NSAD scores across our 3 patients. We see 4 points, 6 points and 7 points, respectively, in our first 3 patients for a mean of 5.7 points compared to baseline. So we're consistently seeing a durable effect at 18 months. We previously shared our 1-year data [ and we can see ] improvement. Now turning to all of our timed function test. These are functional outcomes for cohort 1, again, specifically. What we're showing here is comparison from baseline to month 18. And what you can see again across every single measure, we see an improvement. And this includes our timed tests where we see a decrease in time to do these particular activities, including time to rise, 4 stairs, 100-meter and 10-meter with consistent improvement in all functional measures. Now turning to our data for cohort 2 or our high-dose data showing the NSAD. What we can show here is that we're seeing an improvement in just 6 months of 3.7 points on the NSAD across our 3 high-dose cohort patients. And when we look at all of the functional measures, again here going from baseline to 6 months, we see an improvement in all of our timed tests as well for every single patient across the cohort. Next, what we did was do a summary or a comparison of the mean improvement from baseline to 6 months just -- for both cohort 1 and cohort 2. So this is looking at just 6 months. And what you can see is that as expected with an increase in beta-sarcoglycan expression, we see a subtle improvement in -- at 6 months for cohort 2 for 3.7 versus 3 in NSAD at that time point. And across all of our timed function tests, we're seeing an improvement as well. So just to conclude, durability is an important consideration for a onetime treatment, such as gene therapies. The durability of transgenes delivered via AAV vectors has been observed across programs. We've shown it here in our muscular dystrophy program. Muscle really is an ideal target for durable gene therapy due to the low cell turnover in muscle. And accordingly, higher expression levels protecting more muscle fibers should lead to a more durable functional response. We've shown preclinical data from both our micro-dystrophin program and our LGMD2E program that supports these durable functional responses post gene therapy transfer. And clinical data from both our micro-dystrophin SRP-9001-101 study and the SRP-9003 program support durable functional outcomes at 2 years for 9001 and 18 months for 9003, respectively. And with that, I will hand it over to Doug to lead the question-and-answer session.

Thank you, Louise. Let's open the call for questions.

[Operator Instructions] Our first question comes from Ritu Baral with Cowen.

And congrats on the update. I do have a question on the GGTs across both programs. We usually see ALT, AST elevations with gene therapy programs. I'm wondering what do you think GGT means. Were there concurrent [ ALP ] cross-elevation? Does that lead to -- should we be thinking about cholestatic dysfunction, the kind that was sort of -- sorry, mentioned in the [ XLMTM ] posters at World Muscle this morning as well.

Go ahead, Louise.

Sure. Thank you for that. So one of the reasons with GGT specifically is because AST and ALT are elevated in Duchenne, also in limb-girdle. And so GGT is more sensitive to look for changes that are specifically related to liver versus muscle. So that's generally the reason that we use it. We don't see any specific abnormality in GGT, for example, that would be concerning. It's just more sensitive in this indication.

Our next question comes from Anupam Rama with JPMorgan.

Just a quick one from us on, if you can provide any more granularity on where the NSAA improvements are coming from for the 4 patients. And as we're thinking about kind of the update early next year for the Phase II, is that kind of level of detail something we might expect?

Yes. Louise, do you want to take that?

Sure. Yes, we're seeing improvement across all the NSAA measures. So there's nothing specific yet. This is something we may parse out later in 102 to look for trends. But we're not seeing certain aspects that are not being improved, for example. So we see consistent improvement across those measures for components of the NSAA.

One can -- and you could expect that level of detail when we announce 102. We'll certainly be transparent about 102 when we release it. One of the exciting things about this data is that we're seeing fairly dramatic results, but we're also seeing those results fairly consistently across all of the participants and all of the measures and even in the subcomponents of NSAA.

Our next question comes from Gena Wang with Barclays.

Maybe, Doug, I wanted to ask a one big picture question. So we did see the Complete Response Letter from BioMarin and also we saw FDA requesting another clinical trial for Zolgensma. And I believe those are the same division on CBER. Just wondering, with your regulatory interaction, did you see anything changing or FDA become more stringent? And also any update regarding the pivotal study, the trial initiation?

Yes. So answering the last question first. We don't have an update yet. You can imagine, given that we are [ scrubbed ] and we moved with some speed, we are not being dilatory, but we still have work to do, and we don't have an update yet on the commencement of our next trial and the resolution of -- primarily this assay issue that we've discussed before. It is an interesting question. As it relates to the agency and whether the agency at some level has changed or increased or become more conservative in its approach to gene therapy over the last 2 years, what I can tell you is that Dr. Peter Marks, who is obviously in charge of CBER, who has some years ago, probably in the last 2.5 to 3 years ago, set the stage for the approach the FDA was going to take towards gene therapy and then, of course, spearheaded some guidances that showed an enormous amount of flexibility with respect to gene therapy, has repeatedly, as recently as late last week, reconfirmed that there has not been any change in the FDA's approach to gene therapy, including the willingness to be flexible and to work with companies to advance gene therapies. So at least from our perspective, from the leadership of the agency, presumably that will bleed down to the rest of the division. Dr. Marks continues to make the same comments about the opportunities to be flexible, the willingness to look at things, which is similar to what was done with respect to AveXis, Zolgensma and the like, and we're confident that he means that. What is also true, certainly, is that we're in the middle of a pandemic with the division that was already under an enormous amount of pressure given the workload of cell and gene therapy relative to the staff available. So that may be part of what folks are seeing when there are -- it is difficult at times to have direct or informal conversations with the division. But as far as the broader perspective, we certainly take Dr. Marks' word that the division remains completely committed to advancing cell and gene therapy by being flexible and thoughtful and working closely with companies, not unlike the approach that they took with Zolgensma and before that with Spark.

Our next question comes from Brian Skorney with Baird.

The percent predicted analysis that you guys gave for the 100-meter measure was really helpful. It's a great idea of how the patient is improving relative to where kids without DMD would be on that age. Do you have any frame of reference for the North Star Ambulatory Assessment as a percentage predicted? Or maybe if you kind of give us an idea of where on sort of a natural history curve score of 30 or more is translating to in terms of the [ H-micro-dystrophin ] normal dystrophin expression. Or maybe if there's any data -- I know it's a small patient population but any data on the natural history [ backwards ] to compare it to, that'd be really helpful.

Louise, you want to take that one?

Yes. So thanks for that question. As you know that the NSAA with a max score of 34, that's maximum. And there's certainly normal individuals, there's a range of normal around that. So that's something that we'll certainly look at over time. We don't have the same amount of natural history data represented and percent predicted for NSAA like we do for the 100-meter. But it's certainly a good point to call out that we -- the 34 is the max scale. But yet not every individual -- normal individual that's not DMD isn't scoring a 34. So that's something that we'll look at over time.

Our next question comes from Vincent Chen with Bernstein.

I was wondering if you could comment quickly on the progress you've made in getting approval from the FDA to initiate study 3. I was wondering, for example, have you received any incremental clarity from regulators on what potency assays would be accessible? And if not, I guess, what are the next steps and the range of timing as you see it now for when you might get the clarity? Is there some sort of meeting or discussion that you would need to schedule? Is it just a matter of more informal chats to the regulators? Or would this be something where you'll just go ahead and propose a potency assay once you have what you think is likely to be to the answer validated and so forth?

Doug, you're on mute.

Apologies for that. Everything I just said was brilliant, but I'm going to say not as good now. So thanks for the question. And obviously, I don't -- as I said before, I don't have an update right now on the timing or the outcome of those discussions with the agency. You will know, certainly, if you know Sarepta that we have done a lot to resolve this issue and to get dosing. There are really probably broadly speaking 3 possibilities in timing. I cannot risk analyze or give you probabilities of success of which these will work. But the longest time -- if we had to go down the longest, most formal process, it would be a formal dispute resolution process. Our own history would say that's about a 4-month process. Another formal process that doesn't take as long that we would have a right to, of course, is a type A meeting, that is -- on the outside, it's about a 60-day process. But there is definitely also the possibility, I can't say what the probability is, but the possibility of coming to an informal resolution short of the type A meeting. We are working across these various options and working to engage with the agency. And so we will, I promise you, give an update when we have information and better clarity on what the resolution would look like, and for instance, where we end up with the assay issue.

Our next question comes from Alethia Young with Cantor.

Congrats on the progress. Can you just talk a little bit about maybe between 2 studies, if you're seeing kind of differential activity based on age? I know it's a relatively small sample size, but just wondering if you think that this suggests a broad activity. Or does it kind of -- does it work a little bit different if you're a little older? And then just also, how does this impact your confidence into the first pivotal study?

Before Louise speak, I will say broadly, and then we can give more insight. I mean we are excited about the fact that if you look across these 2 relatively similar disease states and treatments that are very similar, rh74, same promoter and then, of course, gene that codes for a missing structural protein, there's a lot to be excited about in here. The age range is broad in a small data set. So we do see benefit across a large group of children. Some of other children in the LGMD trial are in their, if not teens, almost teens. And we're talking about children who are over 50 kilograms. And we're very excited about the fact, of course, in addition to the functional benefits that we're seeing significant genome copies per nucleus across both groups. But with that said, I'll turn it over to Louise to provide a more nuanced perspective on this.

Thank you. Doug captured it well. I'll just add that this really gives us a lot of confidence in our platform for the use of rh74 and MHCK7 promoter. I think the limb-girdle study makes us very pleased because we're seeing in a large age range and a large weight range, similar effects. So we're not seeing differences in terms of expression or in the function with age or weight. And so that is a lot of reads to both programs and something that we're quite pleased about. Obviously, these are -- this is a small study, but it gives us a lot of continued confidence in this platform moving forward.

Our next question comes from Tyler Van Buren with Piper Sandler.

I guess I just had a follow-up on the 2-year DMD NSAA data. Was there anything, I guess, specific with patient 1 that caused the decline in the functional score from year 1 to 2? And I guess conversely, anything unique about patients 2, 3 and 4 that caused them to see that nice increase in year 2? And you talked about durability of transgene expression going out to 8 years. Would you expect to see another jump up in year 3? Or would you expect functional improvement to ultimately top out?

Louise?

Sure. So for the NSAA, what we see in patient 1 is really just some small variability as we've seen in some other patients for -- at one time point and it's down 1 point and then it's gone way back up. So we're not concerned about that at all. And when you look at the totality of data, specifically patient 1 has continued to improve on all of the other measures as well. So we're continuing to be pleased about the sustained benefits across -- for all patients across all of the measures. And the second part of the question, I think, was on an improvement, right, above the year. So we're certainly continuing to look for sustained benefit and potentially additional development milestones over time.

Our next question comes from Salveen Richter with Goldman Sachs.