BridgeBio Pharma, Inc. (BBIO) Earnings Call Transcript

[Presentation]

Good morning, and welcome to the BridgeBio webcast on our LGMD program. I think this video highlights our mission and why we're dedicated to developing a therapeutic for these patients. Before we begin, I'd like to remind the audience that we will be making forward-looking statements, and you can consult our financial statements for more information. This is a very exciting time for our LGMD program. The Phase III is fully enrolled, and we're expecting data from the interim analysis later this year. That data will support our accelerated approval strategy. The timing today to educate investors on the program is a good opportunity in advance of the International LGMD Conference next weekend. Our agenda today will feature 3 speakers. The first speaker will be one of the top KOLs in the field, Dr. Wicklund, who will walk through the disease background. Our Chief Medical Officer, Dr. Doug Sproule, will address our therapeutic hypothesis and clinical development. Dr. Sproule is a neuromuscular specialist by training and has treated these patients for several years before moving in the industry. He was instrumental in the development and approval of ZOLGENSMA for spinal muscular atrophy before joining BridgeBio. After Dr. Sproule's comments, I'll address expectations for the data readout and the commercial opportunity. We'll conclude with questions and answers. Now it's my privilege to introduce Dr. Wicklund. He is a Professor of Neurology and Vice Chair of Research at the University of Texas at San Antonio. He has participated in over 35 multicenter clinical trials in the areas of muscular dystrophy, ALS and myasthenia gravis. He has over 200 published articles, chapters and abstracts, and invited lectures at national meetings. We're honored to have you join us today. I'll now pass it on to you, Dr. Wicklund.

Good morning. We're going to be talking today about LGMD2I/R9 FKRP-related, which is one of 30-plus subtypes of limb-girdle muscular dystrophies, and each of these muscular dystrophies is driven by a distinct gene, which impacts muscle function. So just to go through this table here, we're going to be talking about LGMD2I, which is the old nomenclature. The gene is FKRP for fukutin-related protein. And the new nomenclature is LGMDR9 FKRP-related. In 2018, it was published, the new nomenclature. And if you look at the old nomenclature, it was LGMD for limb-girdle muscular dystrophy, 2 for recessively inherited and I for the order in which the chromosomal locus was delineated. In the new nomenclature, it is now LGMD for limb-girdle muscular dystrophy, R for recessive, then 9 which is the order in which the gene was discovered, and then we state the name of the protein and call it FKRP-related. So LGMDR9 FKRP-related. The affected gene and protein, the gene is FKRP, and the protein is fukutin-related protein. And it's important to remember that we'll be using this hybrid term often, LGMD2I/R9, and that allows audiences that are familiar with the old nomenclature and the new nomenclature to understand what we're talking about. As we move to the next slide, you'll see in this figure on the left that there is F-actin at the bottom, and that is part of the contractile apparatus of the muscle. And if you look in the mid-portion of this diagram on the left, you'll see the cell membrane, and bridging between the contractile apparatus, F-actin, and up through the cell membrane is that purple structure, which is dystrophin, which many of you may know about as being associated with Duchenne and Becker muscular dystrophy. And so dystrophin helps to bridge between the contractile apparatus and hold that to the cell membrane. And once you get to the cell membrane, you'll see in pink, beta, which is beta-dystroglycan. And just above that in pink also, alpha, which is alpha-dystroglycan. And off of that, you'll see these small structures, which are glycosylation units. And so FKRP is involved in producing the matriglycan portions of it, which is this glycosylation units, and that helps bridge between alpha-dystroglycan up through those glycosylation units, the matriglycan, up to laminin, which then anchors in the basement membrane. And so just as F-actin is attached through the cell membrane with dystrophin, the cell membrane through alpha-dystroglycan and this glycosylation up through laminin is anchored up into the basement membrane. And you can kind of think of that as sort of a velcro, where you have pieces of the cell membrane with portions sticking up and then the basement membrane sticking down and they interlock together and they hold together. In LGMD2I/R9, you'll see on the right, the challenges that the enzyme that glycosylates alpha-dystroglycan does not work as well. So there's hypoglycosylation. And so you have many fewer of those little velcro strands sticking up to attach and you have a less secure attachment between the muscle membrane and up through the basement membrane. So reduced glycosylation of alpha-dystroglycan does result in a muscular dystrophy and including the progressive muscle damage seen in LGMD2I/R9. Now we can see on the left of this next slide that at the top of that figure is the yellow extracellular matrix. And then at the bottom of that is a dark muscle cell membrane. And you see all the little interconnections between those in the healthy muscle tissue. And when you have a contraction, often you'll have a very small membrane tear. So that's the -- tearing it down to build it back up, building strength, but those small little rents are easily repaired in normal healthy muscle. In LGMD2I/R9, you have many fewer of those interconnections, and that leads to small membrane tears and then also larger membrane tears. And these larger membrane tears are much more difficult to mend, and that leads to muscle damage, inflammation and then fibrosis. Now we'll see LGMD2I/R9 does have an established genotype/phenotype association. Roughly 2/3 of patients are homozygous for the common founder effect mutation, which is denoted as L276I. And L276I is a founder effect mutation, which is in Northern European populations, and that's why it is prevalent in the U.S. and in Northern Europe. If we look at this diagram here in the upper left portion, you'll see that roughly 2/3 of patients are homozygous. So they have 2 copies of L276I, and this results in a slightly less severe muscular dystrophy such that at birth, these patients are asymptomatic early childhood, they're asymptomatic in their later childhood and adolescence, they'll begin to develop weakness in the proximal muscles of the legs. And then as they get older in adolescence and adulthood, roughly 1/4 will lose the ability to walk independently by age 40, and they'll develop respiratory and cardiac dysfunction. If you look at the bottom left of this diagram, you'll see that roughly 1/3 of patients have a phenotype that either includes one copy of the common founder mutation, the L276I, with another mutation that is non-L276I or it has 2 non-L276I mutations. And these patients tend to have a more severe phenotype, they are asymptomatic at birth, but in their single digits, they develop weakness in the hip girdle. And so they're a faster progression and they'll develop difficulty with walking in their later childhood and teens. And the vast majority will have lost the ability to walk independently by the age of 20. They have more severe respiratory involvement and roughly 2/3 of them will develop cardiac dysfunction. Diagnosis of LGMD2I/R9 generally follows the pattern of a patient developing some weakness as a child or as a teen. They'll often be seen by their primary care provider and then perhaps sent for physical therapy. And then eventually, they will see a pediatric neurologist or a neuromuscular specialist. And at that point, it's fairly straightforward for us because when we see that patient and we suspect there's a genetic muscle disease, now we will go straight to genetic testing and we're fortunate to have 2 sponsored genetic testing programs, which include the gene for LGMD2I/R9, which is the gene FKRP. Standard of care therapy for these patients is supportive care. This includes physical therapy, cardiac monitoring and management of cardiomyopathy, respiratory monitoring and monitoring for spinal deformities. The key unmet need in this population and for all LGMDs is that there is no disease-modifying therapy that can slow or stop the progressive decline experienced by these patients. So in summary, LGMD2I/R9 FKRP-related is one of many genetically distinct subtypes of limb-girdle muscular dystrophy, but is one of the most common of the limb-girdle muscular dystrophies, and it causes progressive muscle weakness including involvement of skeletal muscles, which is loss of ambulation; cardiac muscles, which is the cardiomyopathy; and respiratory muscle, which is the respiratory dysfunction. The foundational defect in LGMD2I/R9 is mutations in FKRP that reduce the function of the FKRP enzyme, which results in decreased glycosylation of alpha-dystroglycan. Standard of care therapy is supportive care and supportive care does not stop the progressive decline experienced by individuals living with LGMD2I/R9. I'll now turn the presentation over to Doug Sproule, Chief Medical Officer.

Thank you, Dr. Wicklund, for those excellent remarks and lead in on the symptomatology and background of LGMD2I/R9. Moving to Slide 11. I wanted to take a moment and really celebrate the remarkable progress that has occurred over the last several decades, and particularly in the last several years, moving us from a world where limb-girdle muscular dystrophy was a description of clinical symptoms to the understanding of the complex genetic underpinnings of these discrete forms of limb-girdle muscular dystrophy, the identification of FKRP as the genetic etiology of LGMD2I/R9. And moving from that and our understanding of how this enzyme functions and the critical role it plays in the glycosylation of alpha-dystroglycan to being able to identify potential therapeutic strategies, the identification of BBP-418 as a potential therapeutic strategy to treat this disease. And moving very expeditiously into human trials in 2021. We started our Phase II study in patients with LGMD2I/R9. And starting in 2023, we started the -- our Phase III randomized, double-blind, placebo-controlled trial of BBP-418 in LGMD2I/R9. And as Christine Siu noted at the outset, we're very excited to have fully enrolled this study and are anticipating the release of interim data later this year. If you move on to Slide 12. BBP-418 is being investigated to target the disease, LGMD2I/R9, at its source by driving the residual activity of affected FKRP enzyme and restoring the effect of glycosylation of alpha-dystroglycan. So what actually happens? On the left side is the disease mechanism that Dr. Wicklund very eloquently described. In the untreated disease state, you have normal physiological levels of CDP-ribitol, which is the effective substrate of FKRP. And in the context of mutation to FKRP enzyme that there's an inadequate and dysfunctional glycosylation of alpha-dystroglycan that occurs. And so only a very small percentage of the alpha-dystroglycan glycoproteins are effectively glycosylated. And this leads to that situation where there's membrane instability, susceptibility to injury with routine and potentially significant muscle contraction leading to chronic injury, cell turnover, loss, inflammation, scarring, adipose tissue replacement and the panoply of changes that underlie a muscular dystrophy. Our proposed therapeutic approach is to supply a super physiologic levels of a synthesized pharmaceutical-grade form of ribitol called BBP-418, and this is meant to drive increased supraphysiologic levels of CDP-ribitol, the effective substrate for FKRP in the cell. And while those -- that FKRP enzyme is dysfunctional, there is still some residual activity that you can harness through this approach and drive forward increased glycosylation of alpha-dystroglycan. And if sufficient, you can increase glycosylation to a degree to potentially ameliorate, slow, potentially halt or potentially even allow healing and ultimately, clinical improvement to occur. And this is the, I would say, elegant disease-specific, mechanism-specific strategy that underlies our program. If you can go to the next slide, which is Slide 13. And one of the critical things that allows us to assess the effectiveness of this therapy is that we have developed a proprietary validated Western blot based bioassay that allows us to directly measure glycosylated alpha-dystroglycan and skeletal muscle tissue. And what you see here is that using this assay, you can see very clearly in the color, the yellow signal corresponds to functional laminin binding form of glycosylated alpha-dystroglycan. And so this is functionally effective form of alpha-dystroglycan. And what you see on the left column, which is an untreated patient, is that there's really limited yellow, limited evidence or limited levels of glycosylated alpha-dystroglycan that are seen in this patient's muscle biopsy sample at baseline prior to treatment with BBP-418. In the middle column, you see the response at 3 months. On the right column, you see the response at 6 months. And you can see that increasingly bright yellow signal, which is indicative of a marked increase in glycosylated alpha-dystroglycan following administration of this therapeutic approach. We are adapting and utilizing this bioassay in our natural history study, but also in our Phase II and most critically, in our Phase III study to demonstrate the effect following treatment with BBP-418. And in the case of our Phase III study, to demonstrate, we hope and expect a significant difference between patients treated with BBP-418 and patients treated with placebo. We've met with the FDA. And I'll talk about this more at the end of my section. But they have been very receptive to this approach, and they've indicated that our approach to measure glycosylated alpha-dystroglycan using this validated assay appears reasonable and potentially could serve as a basis as a surrogate biomarker as a basis of an accelerated approval proposal. If you go to the next slide, Slide 14. I'm not going to go into the weeds on this slide. There's a lot of details, but we've conducted a number of studies. This is the comprehensive clinical development program, especially for a rare disease to evaluate the safety and signals of efficacy for BBP-418. This includes a large natural history study that we used to help characterize the disease and establish our -- and validate our muscle biomarker bioassay. We've done 3 Phase I studies in healthy volunteers. A small open-label Phase II study, which has been ongoing for several years now and gives us longer-term clinical and safety data as well as evidence related to our biomarker, and I'll talk about that more in the next several slides. And of course, we have our large ongoing, fully enrolled Phase III study, MLB-01-005 or FORTIFY, which is fully enrolled in September of last year and we expect an interim analysis top line data readout later this year. So if you go to Slide 15, this is data from our natural history study. And as Dr. Wicklund described, patients who are homozygous for the L276I mutation, the common or so-called "Viking" mutation, tend to have less severe clinical symptoms than patients with other commonly more severe genotypes. And then how patients respond or patients' muscle tissue is measured using our bioassay. And so on the left side, you see, in the darker green, the distribution of glycosylated alpha-dystroglycan levels in patients who are homozygous for L276I. And the median is around 11% of a healthy control reference standard. So markedly reduced glycosylated alpha-dystroglycan levels when compared with a healthy controlled standard unaffected by this disease. In contrast or in addition, patients with other genotypes have an even more reduced level of glycosylated alpha-dystroglycan on average or a median level of 4.5% of, again, of that reference standard. And this is consistent with what we would expect to see given the differences in clinical symptoms between these 2 populations. We're able to demonstrate that this is a reproducible -- these are reproducible values, and this established a strong basis for us to utilize this approach in our clinical studies. If we can go to the next slide, which is Slide 16. This slide depicts our Phase II study. This is a dose escalation study. There was a 90-day dose escalation period. We enrolled 3 cohorts of a total of 14 patients in a dose-escalating manner. After that first 90 days, all patients were advanced to 12 grams twice a day, dose adjusted for lower-weight patients, which is our proposed therapeutic dose that we've utilized in our Phase III study. This is a -- it's an open-label study. There are only 14 subjects, but we are able to measure a wide array of clinical endpoints, including the NSAD, which is our primary endpoint in our Phase III study. Ambulatory measures, ventilatory measures, upper limb measures and critically, the impact on glycosylated alpha-dystroglycan as well as creatine kinase, which is a widely used marker of muscle injury that's broadly used in the neuromuscular community. This was a study -- had broad studying criteria, included adolescents and adults and patients who are both homozygous for L276I as well as patients with other genotypes. It also included some nonambulatory patients as well. So it gives us a broad snapshot of which we can assess the potential effectiveness and safety of this therapy across a broad population. So moving on to Slide 17. This slide depicts the safety data to this point in the Phase II study. BBP-418 has been well tolerated to date with only minor gastrointestinal-related adverse events that have been recorded in this study. You can see the depiction on the right. Most of the reported treatment-emergent adverse events in the Phase II study were grade 1 or grade 2 in severity, largely gastrointestinal in nature, which is unsurprising based on the pharmacology of the product. We experienced no discontinuations or interruptions of therapy in the Phase II due to adverse events. And to this point, we're very reassured that this product has a well-tolerated risk profile and safety profile to this point and may -- this may provide a foundation for a very favorable risk-benefit ratio for patients. If you can move to Slide 18, this shows the data from the bioassay on the left and creatine kinase on the right. We have observed sustained and marked increases in glycosylated alpha-dystroglycan levels in the muscle biopsy samples from patients with -- treated with BBP-418. And commensurate to that, we've seen decreases in serum creatine kinase in treated patients in the Phase II study with BBP-418. And this shows that this -- and suggests that there is an impact physiologically at the level of the muscle cell that's translating to reduced muscle injury at the level of the muscle organ. So if you look on the left side of the figure, the darker green depicts the cohort of patients who are homozygous for L276I. The patients experienced an increase from an approximate median of around 16.5% to around 40% of that reference standard indicative of more than doubling in the median response in patients homozygous for L276I. For patients with other genotypes, as would be expected, these patients start from a much lower baseline, the median level of approximately 6% of that reference standard increasing to approximately 10% of that reference standard after 6 months of therapy. Similarly, and kind of carrying through and supporting the observations that we see on the bioassay, we've seen a marked reduction of more than 80% from baseline in serum creatine kinase that has been sustained on repeated sampling over well more than a year of clinical follow-up. And so this suggests that we're seeing an increasing glycosylated alpha-dystroglycan at the level of cell, and that's leading to reduced muscle injury and muscle breakdown in patients treated with BBP-418 indicated by this marked and sustained reduction in creatine kinase. This gives us, obviously, a lot of confidence and a lot of enthusiasm on the potential for this therapy to make a significant clinical impact for patients. If you can move to Slide 19, we're seeing a translation and a flow through to clinical measures as well. These 2 figures depict 2 ambulatory measures. On the left is the 10-meter walk test, which, as would be suggested, is the time to walk 10 meters. On the right is a 100-meter timed test, which is the time it takes for a patient to transit between 2 cones, 25 meters apart, back and forth twice. So what you see on the left in the red dashes is the response in patients treated with BBP-418 in the Phase II study, and you see an improvement in velocity on the 10-meter walk test that stabilizes over time. And this compares very favorably with the trajectory that's depicted in the solid blue, which are the patients from the ML Bio sponsored natural history study. And similarly, on the right, you see an improvement in the performance on the 100-meter timed test amongst treated patients, again, in the red dash lines when compared with the downward and declining trajectory that you see in patients who were followed in an untreated fashion as part of the MLB-01-001 natural history study. So this suggests that there is a clinical impact that we're seeing and it goes beyond the significant and intriguing biological impact that we're already observing. And this has led us to proceed into a large Phase III study. This is moving to Slide 20. And we have fully enrolled our Phase III study in September of 2024. This is a study called FORTIFY. It's assessing the safety and efficacy of BBP-418 for patients with limb-girdle muscular dystrophy type 2I/R9. And we expect to see top line interim data that will be available in the second half of this year, and we're obviously very excited to see what emerges from this interim analysis. Speaking very kind of broadly and generally, this study enrolls adolescents and adults, 12 to 60 years of age, patients who are genetically confirmed with LGMD2I/R9. It's randomized 2:1 to treatment versus placebo. And we expect that we'll be performing an interim analysis looking at approximately 70 patients who have completed at least 12 months of clinical follow-up at that point. This study is 36 months in total duration. And the final analysis will be based upon -- will be performed at that time based upon several endpoints, particularly the North Star Assessment for limb-girdle muscular dystrophy, which is our primary endpoint. This is an endpoint, a gross motor function endpoint that's favored by the regulators, particularly the U.S. FDA. It is a measure that while we expect it will strongly demonstrate the impact of our therapy, if it is indeed efficacious over a 36-month period, it challenges with sensitivity and variants over shorter intervals, which is the reason for our longer-term study. We're very excited, however, to be looking at an interim analysis that will be based on the response on our bioassay, glycosylated alpha-dystroglycan levels, as well as looking at laboratory measures, specifically creatine kinase and trends and impact on selected clinical measures at 12 months. And we are expecting to engage our regulatory partners following those results to discuss a potential pathway for an accelerated approval. So if we go to the next slide, which is Slide 21. Reinforcing that, we've had several engagements with the FDA regarding this strategy, and we've received positive feedback from them on the potential for an accelerated approval pathway based upon the utilization of glycosylated alpha-dystroglycan as a surrogate endpoint of clinical impact. And this -- the FDA can utilize this approach using a surrogate endpoint such as glycosylated alpha-dystroglycan in this disease. The premise is that this marker would carry biological plausibility, it has reliability and measurement and its associated with clinical outcomes that are of importance to patients. And we believe and we've engaged the FDA on this point that glycosylated alpha-dystroglycan measured in muscle tissue of patients with this disease is a very effective and reasonable biomarker that meets that criteria. So if you go to the next slide, Slide 22. To kind of summarize my section, BBP-418 aims to target LGMD2I/R9 at its source by restoring glycosylation of alpha-dystroglycan, which we can measure using a proprietary validated bioassay that we have utilized both in our natural history study, our Phase II study, as well as in our ongoing Phase III study and discussed at significant detail with our -- with the FDA and other regulatory partners. In a small open-label Phase II study, we've shown that the BBP-418 has been well tolerated and has led to sustained improvement in glycosylated alpha-dystroglycan and reduction, which is an improvement in serum creatine kinase. We've also observed trends towards stabilization and improvement in ambulatory measures when compared with downward and declining trajectory that we see in untreated natural history populations. And consistent with the positive feedback from the FDA, our fully enrolled Phase III study, FORTIFY, has been designed and is being executed with a planned interim analysis that will occur following 12 months of clinical follow-up that is focused upon assessing the impact on glycosylated alpha-dystroglycan as a surrogate endpoint that would support a potential accelerated approval pathway in the United States. And with that, I will pass the baton to Christine Siu, our CEO, and thank you for your attention.

Thank you, Doug. Continuing the momentum from the Phase III study, we've had a number of milestones bringing us to today. As Doug mentioned, we've had multiple encouraging FDA discussions where they've indicated the potential for accelerated approval using glycosylated alpha-dystroglycan as a surrogate endpoint. We published a manuscript on the proprietary assay that we developed to measure glycosylated alpha-dystroglycan. And just as a reminder, we've also saw FDA feedback on this assay and they indicated that it was reasonable to measure the primary end point. We fully enrolled to the Phase III study. This was a really encouraging achievement as it was completed 20% over enrolled and completed 8 months ahead of time. So that was pretty exciting. And that brought us to -- that brings us basically today where we're expecting the top line data later this year. So what do we expect in the top line data? On the next slide, we're demonstrating that we do expect a robust effect on the biomarkers on glycosylated alpha-dystroglycan as well as CK. For glycosylated alpha-dystroglycan, we're expecting a statistically significant increase versus placebo. We'd like to see an absolute increase of 5% or more change from baseline in treated patients. In CK, we'd like to see an average decline of 40% or more change from baseline in treated patients. In terms of the functional measurements that we're looking at, we'd be pretty pleased if we saw a trend in one or more of them. It's important to note that we do not expect statistical significance in any of the clinical outcomes. The study wasn't powered to show that at 12 months. And also very importantly, it's important to note that the FDA has indicated they do not require statistical significance on any of the clinical outcomes at 12 months since it is not expected. In terms of the safety profile, we expect to see a well-tolerated profile consistent with our Phase II results. And if we saw all of this, we would file an NDA for accelerated approval. Moving on to the commercial opportunity on Slide 25. We believe that this is a large market opportunity. It's represented by about 7,000 patients in the U.S. and EU. We're excited about the opportunity to be the first to market with a disease-modifying safe oral therapy. On the next slide, we really just break down the patient prevalence estimates in a little bit more detail. There is a founder mutation for this disease that exists primarily in people of Northern European descent. As you extrapolate the prevalence in that population to the relative population in the U.S. and Europe, that's where we come out kind of with our 7,000 patient number. If you couple this with our anecdotal experience of enrolling our Phase III study really so quickly ahead of time, it gives us a lot of confidence that there's a pent-up demand for therapy and patients really wanting access to therapy. It's also interesting to note that this market is comparable or larger than the exon 51 skipping market that was the initial target for DMD drugs. On Slide 27, we're showing some of the work we're doing through community engagement to increase patient identification. We have partnered with several patient advocacy organizations. There are several natural history studies that have been run including our own or that are also ongoing, and those have helped increase patient identification as well. On Slide 28, we're just highlighting several of the tailwinds that we could benefit from for developing the market. As Dr. Wicklund spoke about, there are a couple of sponsored genetic testing programs already out there that helps with genotyping the patients and confirming diagnosis. Recently, there was an ICD-10 code approved, specifically for LGMD2I/R9, and that will help again with diagnosis and eventually reimbursement. There are also other therapies being developed for other genetic forms of LGMD and that could help drive patient identification and disease awareness as well. So with all of that, we're very excited to be at this place now with data later this year that could support an accelerated approval, potentially delivering a first-to-market disease-modifying therapy for patients sooner rather than later. We will now open it up for Q&A, and you could submit your questions in the portal.

Our first question today is for Dr. Wicklund. What, if anything, is distinctive about LGMD2I/R9 relative to other LGMDs?

Sure. To chat about that, a couple of things come to mind. One is it's one of the most prevalent of the limb-girdle muscular dystrophies. So it has a higher prevalence than the majority of them. And then from our standpoint, as treating providers in limb-girdle muscular dystrophy, the ones that have cardiac and respiratory involvement, those are the ones that significantly impact in terms of morbidity and mortality. And so those are the ones that we care about the most. So those are 2 key features. It's quite prevalent amongst the LGMDs and then also it has significant cardiac and respiratory involvement.

Okay. The next question, what are some of the most common reasons that LGMD2I/R9 patients might be undiagnosed today? Do you anticipate approval of a therapy would lead to additional patients receiving a genetically confirmed diagnosis? Maybe, Dr. Wicklund, you could take that question as well.

Sure. Some patients previously seen for a generic diagnosis of LGMD who were without a genetic diagnosis since there was not any disease-specific treatment, they just simply stop coming into clinic because they really were not getting much out of it other than supportive care, which many of them could do on their own or elsewhere. Additionally, other patients are followed in other clinics such as primary care or rheumatology. And those patients most often do not have a genetic diagnosis. And yes, we have seen in other disorders that once a treatment becomes available, many patients do flock back into the clinic seeking care. And a good example of that was over 10 years ago when we had patients with Pompe disease and we finally had a treatment, and we found many of them return to treatment to seek care because of the treatment that we had available.

Okay. Our next question, it's a compound question here. Based on the inclusion/exclusion criteria for FORTIFY, how representative are patients enrolled in the trial of the broader LGMD2I/R9 population? What degree of change would you expect in functional measures between the interim and final analysis? Maybe, Doug, you can take that question?

Yes, certainly. So obviously, it's a complex and complicated question. With regard to the population, the study was designed to optimize a data readout on the NSAD and is weighted towards higher functioning patients. There are a certain number of nonambulatory patients who are also included in the study that gives us confidence that should the data demonstrate clinical effect that we would aspire and expect to have a pretty broad label around function as well as a broad age range from 12 years and up. With regard to what we expect to see from the standpoint of the clinical study, it is anchored around a premise that stability is an important achievement in these patients. What we have routinely and repeatedly heard from the patient community is that while they would love to experience and enjoy an improvement from their current symptoms, what they fear is what they're going to lose next. And so the study is powered and designed around a premise of stability. We see in the natural history study in a relatively modest but continual and accretive decline in function that's seen over time. And so we expect that on the primary endpoint, which is the NSAD that we'll see over the course of the study amongst untreated patients, somewhere between 3- to 5-point decline, which is a robust window in which it demonstrates stability and which is our aspiration in untreated -- or in the treatment arm of the study.

The next question. Has the FDA specified if there needs to be any trend functional data for accelerated approval? Or is this just biomarker focused? Maybe I'll frame the answer first, and then I'll ask if Doug has any comments to add. So consistent with our remarks, the primary endpoint for the interim analysis is the biomarker glycosylated alpha-dystroglycan change from baseline at 3 months. So we are expecting a pretty robust response on the biomarkers, glycosylated alpha-dystroglycan as well as CK. Then we're looking at the functional data. We're looking at trends at the functional data at 12 months. And what's going to be helpful, I think, in terms of totality of evidence to base the accelerated approval on is looking for correlations of the change in glycosylated alpha-dystroglycan at 3 months, looking at those correlations to trends in clinical outcomes at 12 months to get at the idea of it being reasonably likely to predict clinical outcomes. So in our discussions with the FDA, a couple of things regarding the surrogate endpoint, glycosylated alpha-dystroglycan, one, is it biologically plausible, and there's clearly a strong scientific rationale for its implication in the disease and why we believe that basically treating disease at its source could lead to clinical outcomes. And then the second part of the approval strategy is trying to tease out those correlations over time to get at -- it's reasonably likely to predict clinical outcomes. So Doug, I don't know if you have anything to add to that.