It can be quite scary when you think about it. Where am I going to be in 20 years? Where am I going to be? I have to move into an assisted living facility. I mean, that's, I guess, a real possibility I have to consider. Those are all prospects that no one likes to think about.
I was diagnosed at 18. They ran a bunch of tests and told me I had MD, and I said, what do I do? They said there's no treatment or cure, so really nothing. They said, don't exercise too much, you know, take it easy. For 35 years I had my appointment, was going in, asking the same questions and hearing, I don't know.
In 2007, my brothers-in-law, I asked my wife or told my wife, like, hey, there's something, he's getting worse, Rich is getting worse. Please have him checked out. After that, went and got checked out, the CK levels were high and that was a concern, but it was really a heart that got me kind of moving towards a real diagnosis.
We were on a vacation recently and I have two daughters, they're 12 and 15. One of them said to me, we're going to go cliff jumping. You know, can you come up this trail? It was very rough and it does sometimes make me sad. I feel myself getting emotional. Emotional, yeah. Those moments do bring me joy, but I wish I could jump off with them too. You want to be with your family doing what you're doing? I do, I do. You've raised a great point. It's not just us that are suffering. Our families really have to do a lot for us and they have to make a lot of sacrifices. I think that's the part that gets me the most because my husband's been so great and I know it holds him back in many ways and we're happy and we're having fun.
You know, I'm sure there's trips he'd like to take that would completely not be possible and things he'd like to do where he'd like me to join him. I can't do that.
You know, thinking about my future is scary. I face this journey on my own. I live alone. You know, it's very reassuring to know that there are things on the horizon that can change the course of this.
I always kind of had the mindset of, you know, I can handle where I'm at today. By the time this gets super annoying, they'll come up with something. They must be really close because this has gotten really annoying. That's how I know we're close because it is really getting to be a lot for me. Yea.
Good morning and welcome to the BridgeBio Pharma 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 three 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 into 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. Each of these muscular dystrophies is driven by a distinct gene which impacts muscle function. 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, the new nomenclature was published, 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. We state the name of the protein and call it FKRP-related.
LGMDR9 FKRP-related is the affected gene and protein. The gene is FKRP, and the protein is fukutin-related protein. It's important to remember that we'll be using this hybrid term often, LGMD2I/ R9. 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. If you look in the mid-portion of this diagram on the left, you'll see the cell membrane. 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.
Dystrophin helps to bridge between the contractile apparatus and hold that to the cell membrane. 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. Off of that, you'll see these small structures which are Glycosylation units. FKRP is involved in producing the Matriglycan portions of it, which are these Glycosylation units. That helps bridge between Alpha-Dystroglycan, and this Glycosylation up through Laminin is anchored up into the Basement membrane. 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 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.
At the bottom of that is a dark muscle cell membrane. You see all the little interconnections between those in the healthy muscle tissue. When you have a contraction, often you'll have a very small membrane tear. That's the, you know, tearing it down to build it back up, building strength. 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 also larger membrane tears. 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.
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 2/3 of patients are homozygous. They have two copies of L276I. 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. As they get older, in adolescence and adulthood, roughly a 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 a 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 two non-L276I mutations. 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. They'll develop difficulty with walking in their later childhood and teens. 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 teenager.
They'll often be seen by their primary care provider and then perhaps sent for physical therapy. Eventually, they will see a pediatric neurologist or a neuromuscular specialist. 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 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.
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 function like glycosylation that has occurred.
Over the last several decades and particularly 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 be 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 2 study in patients with LGMD2I/R9, and starting in 2023, we started 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 enzymes and restoring the effective glycosylation of Alpha-Dystroglycan. 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 physiologic levels of CDP-ribitol, which is the effective substrate of FKRP, and in the context of mutation to FKRP enzyme, there's an inadequate and dysfunctional glycosylation of Alpha-Dystroglycan that occurs.
Only a very small percentage of the Alpha-dystroglycan glycoproteins are effectively glycosylated. 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 supraphysiologic levels of a synthesized pharmaceutical grade form of ribitol called BBP-418. This is meant to drive increased supraphysiologic levels of CDP-ribitol, the effective substrate for FKRP in the cell. While 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. 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.
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, 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 in skeletal muscle tissue. What you see here is that using this assay, you can see very clearly in the color that the yellow signal corresponds to functional laminin-binding form of glycosylated Alpha-dystroglycan. This is functionally effective form of Alpha-dystroglycan. 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 three months. On the right column you see the response at six months and you can see that increasingly bright yellow signal which is indicative of a marked increase in glycosylated Apha-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.
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 as the common 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 use to help characterize the disease and establish and validate our muscle biomarker bioassay.
We've done three phase one 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. I'll talk about that more in the next several slides. Of course, we have our large ongoing fully enrolled Phase III study, MLB-0105 or FORTIFY, which was fully enrolled in September of last year and we expect an interim analysis, top-line data readout later this year.
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. How patients respond or patients' muscle tissue is measured using our bioassay. 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. There are markedly reduced glycosylated Alpha-dystroglycan levels when compared with a healthy control 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% again of that reference standard.
This is consistent with what we would expect to see given the differences in clinical symptoms between these two populations. We're able to demonstrate that these are reproducible values, and this established a strong basis for us to utilize this approach in our clinical studies. You can go to the next slide, w hich is Slide 16.
This slide depicts our Phase II study. This was a dose escalation study. There was a 90-day dose escalation period. We enrolled three 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 an open-label study. There are only 14 subjects, but we were 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 with broad study criteria, included adolescents and adults, and patients who were both homozygous for L276I as well as patients with other genotypes. It also included some non-ambulatory patients as well. It gives us a broad snapshot at which we can assess the potential effectiveness and safety of this therapy across a broad population. 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 One or Grade Two 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. To this point, we're very reassured that this product has a well-tolerated risk profile and safety profile to this point. 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 treated with BBP-418. Commensurate to that, we've seen decreases in serum creatine kinase in treated patients in the Phase II study with BBP-418. This shows that there's and suggests that there's an impact physiologically at the level of the muscle cell that's translating to reduced muscle injury at the level of the muscle organ.
If you look on the left, if you look on the left side 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% baseline in serum creatine kinase that has been sustained on repeated sampling over well more than a year of clinical follow-up. This suggests that we're seeing an increase in 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, you know, 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 two figures depict two ambulatory measures. On the left is the 10 meter walk test, which as would be suggested, is a time to take time to walk 10 meters. On the right is the 100 meter time test, which is the time it takes for a patient to transit between two cones 25 meters apart, back and forth twice. What you see on the left in the red dashes is the response in patients treated with BBP-418 with the trajectory that's depicted in the solid blue, which are patients from the MLBIO sponsored natural history study.
Similarly, on the right you see an improvement in the performance on the 100 meter time test amongst treated patients again in the red dashed lines when compared with the downward and declining trajectory that you see in patients who were followed as in an untreated fashion as part of the MLB 01001 natural history study. 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. This has led us to proceed into a large Phase III study. This is moving to Slide 20 and we 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. We expect to see top line interim data.
The final analysis 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 p articularly 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 has challenges with sensitivity and variance 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. We are expecting to engage our regulatory partners following those results to discuss a potential pathway for an accelerated approval.
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. 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 in measurement and is associated with clinical outcomes that are of importance to patients. 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.
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 s tudy, our Phase II study as well.
As in our ongoing Phase III study and discussed at significant detail with the FDA and other regulatory partners, in a small open-label Phase II study, we've shown that 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 the downward and declining trajectory that we see in untreated natural history populations. 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 U.S.
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 sought FDA feedback on this assay, and they indicated that it was reasonable to measure the primary endpoint. We fully enrolled the Phase III study. This was a really encouraging achievement as it was completed 20% over-enrolled and completed eight months ahead of time. That was pretty exciting, and that brings us basically to today where we're expecting the top-line data later this year. What do we expect in the top-line data on the next slide?
We're demonstrating that we do expect robust effects 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 five percent 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. 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. 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. If 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 DMT drugs. On Slide 27, we're showing some of the work we're doing through community engagement to increase patient identification. We 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 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'll 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. 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.
It has a higher prevalence than the majority of them. From our standpoint, as treating providers in limb-girdle muscular dystrophy, the ones that have cardiac and respiratory involvement are the ones that significantly impact in terms of morbidity and mortality. Those are the ones we care about the most. Those are two key features. It's quite prevalent amongst the LGMDs, and 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 simply stopped 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. Yes, we have seen in other disorders that once a treatment becomes available, many patients do flock back into the clinic seeking care. 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 returned 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 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. 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 non-ambulatory patients who are also included in the study. That gives us confidence that should the data demonstrate clinical effect, 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. The study is powered and designed around a premise of stability. We see in the natural history studies a relatively modest but continual and accretive decline in function that's seen over time. We expect that on the primary endpoint, which is the NSAD, we'll see over the course of the study amongst untreated patients somewhere between a three to five point decline, which is a robust window in which to demonstrate stability, which is our aspiration in the treatment arm of this study.
The next question, how's 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. Consistent with our remarks, the primary endpoint for the interim analysis is the biomarker of the glycosylated Alpha-dystroglycan change from baseline at three months. We are expecting a pretty robust response on the biomarkers glycosylated Alpha-dystroglycan as well as creatine kinase. We're looking at the functional data, we're looking at trends at the functional data at 12 months.
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 three 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. In our discussions with the FDA, a couple things regarding the surrogate biomarker glycosylated Alpha-dystroglycan: one, is it biologically plausible? There, 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. 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. Doug, I don't know if you have anything to add to that.
Summarizes it really well. I think the one additional point I would add that is part of the premise behind the predictability is also the mechanism of action. With the stabilization, with the increase in glycosylated Alpha-dystroglycan levels leading to s tabilization o f ongoing muscle injury, we would e xpect that y ou can demonstrate that biological impact relatively early. There would necessarily be a delay in time while these patients were able to experience a recovery and regeneration or failure or avoidance of loss of further decline. That further substantiates the premise behind looking e arly at a biomarker as a predictor o f subsequent clinical manifestations.
Our next question, given the high unmet need in this indication that you described during the call, if the data for BBP-418 are strong and lead to statistical significance, what portion of your patients would you plan to prescribe this therapy to? What are the characteristics of the patients that you would not prescribe BBP-418 and what else would they receive? Dr. Wicklund, do you want to address this question?
Sure, I'm happy to do so. We've seen this in other treatments that have come to market, but the answer is we would treat just about everybody. The logic behind that in my mind would be that the mechanism says that it should work in most patients, if not all patients. The other features that are important are the route of administration, so it's just an oral treatment. Finally, most of these patients would be willing to use something that has a very good safety profile. Without significant side effects, I think most of our patients would adopt this. The one place we may see that we would not treat would be the early diagnosed because of genetic testing that are asymptomatic, but those are not clinically active patients at the time that they're genetically diagnosed. I think most patients would wind up getting treated.
Maybe one last thing at the far end of the spectrum, which is the patients that are severely affected, even minor improvements in their motor, respiratory, or cardiac function often have significant impact in their quality of life. We've seen that in our SMA patients that maybe go from being full-time ventilated to being four hours off the ventilator, and that independence and freedom is significant for them.
Thank you. The next question is a two part question. Why do the ambulatory metrics in the Phase II seem to decline over the course of the study? Two, if the Phase III recapitulates these trends on 10 meter walk tests and 100 meter time tests, do the KOLs find it compelling? Maybe Doug, you could answer the first part of the question and then maybe Dr. Wicklund, you could comment on kind of what would be compelling in terms of the ambulatory measures.
Yeah, certainly. I think, you know, obviously the quick answer is I don't think anyone can prove anything. I'll give you the strong theory phase. We've seen this in other neuromuscular disease trials, specifically the Nusinersen type SMA type 2 trial, where you see an early bump from enthusiasm and then a waning over time as the placebo effect that might be attributed to the early response wanes away. I think that what we're seeing in the Phase 2 study, I frankly don't look at what response I'm seeing in the first three to six months. I'm more interested in what I'm seeing nine to twelve months out. What we're seeing is a marked departure from the decline and deterioration that we see in natural history and untreated populations.
With regard to the longer study, I expect that deviation and that differentiation will further accentuate as one looks one year, two years, three years out to the study. The second part of this question. I think Dr. Wicklund might be best equipped to answer. I'm happy to offer my perspective.
Yeah, I'll go ahead and jump in. I think that there will be a significant adoption of use of this medication if we see that there's a change in the slope of progression. Most of our patients, since there's nothing available, would be pleased with a slowing in progression. If we can change the slope at some point and even if there's a bump and then there's a downward decline, there's a decline in function. If that decline in function is at a slower rate such that, you know, five or 10 years down the road, they're not as severely affected, most of our patients, assuming that the route of administration is easy and there's a good safety profile, I think that the adoption will be quite good. The SMA oral medications kind of fit into this category.
Thanks. The next question, could you speak to any recent discussions you've had with the FDA given the changes in management? There, do you retain the same level of confidence in what you'd previously been told? Let me address this question first and then ask Doug if he has anything to add. We've had very consistent interactions with the FDA, which have all been consistent in the potential for accelerated approval using glycosylated Alpha-dystroglycan described as a surrogate endpoint. Given the changes at the FDA recently, we have not seen or heard anything that would be inconsistent with all the collaboration and interactions we've had with the FDA previously. There have been obviously a lot of changes at the top with the FDA. Our review division has not changed. It is the same group of reviewers that we've been interacting with.
In the absence really of anything, any changes that have been communicated to us specifically, we really haven't changed our regulatory strategy. In fact, we collaborate and lean quite heavily as well on the patient advocates as well as the KOLs who have actually come to our FDA discussions with us to really outline and underlie the need for regulatory flexibility in this disease, given the fact that there is nothing available for them and these patients will continue to progress to dysfunction.
Doug, maybe just a few additional points. Obviously, we can't predict the future. We don't know the impact of the changes, but there have been a lot of positive changes from our perspective as well, particularly in some of the voicings from the new leadership over at the agency. Looking back at our program, there's a couple important points. One of them is the incredible and ongoing unmet need here. This is a disease with marked disability and profound impact on life. There's no existing therapeutic options. We are also, from a lot of perspectives, a conservative program. I know the accelerated approval pathway is a very aggressive approach, but compared with other sponsors and other programs, this is a—we've developed a mechanism-specific bioassay and biomarker that's really a strong indicator of therapeutic effect.
We have conducted a large double-blind randomized control trial that's pretty much almost as large as any study that's been performed in the neuromuscular space. I think it's slightly smaller than the Biogen Phase II type 2 study, but very closely to that size. I'm unaware of any larger study that's ever been performed in this space. We are planning to complete this study—not planning, we are going to complete this study. We've met all of the asks and really provided what I would consider bulk, the overwhelming, almost all of the adverse events related to the gastrointestinal upset have been at the start of dosing. The experience has been that following the start of dosing, it's very common to have some GI disturbance. This is something that patients have generally tolerated or tolerate to. This is not something that is seen over the longer term. It's an acute and usually resolving in a very short time. We do not expect it to be an issue in long-term dosing. It has not been an issue in our Phase 2 study.
That concludes our webcast today. Thank you all for joining us.