Ladies and gentlemen, thank you for standing by. My name is Krista, and I will be your conference operator today. At this time, I would like to welcome everyone to the BridgeBio Pharma, Limb- girdle Muscular Dystrophy Type 2I/R9 FORTIFY phase three interim analysis results webinar. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer session. If you would like to ask a question at that time, simply press star, followed by the number one on your telephone keypad. If you would like to withdraw your question, again, press *1 . Thank you. I would now like to turn the conference over to Dr. Neil Kumar, Chief Executive Officer. Dr. Kumar, please go ahead.
Thanks, everyone, for joining this call. Together with our amazing team, I'm grateful to be able to share with you, on behalf of the extraordinary physicians, patients, families, and caregivers involved, the positive phase three results of our FORTIFY clinical trial for patients with Limb- girdle Muscular Dystrophy Type 2I/R9. The strongly positive and consistent data the community worked tirelessly to generate come together at this moment to portend a new and better day for current and future patients struggling with this condition. Before I set the corporate context for this readout, I want to begin with the most important slide in this document, slide four, a thank you to the amazing and inspiring patients and families, advocates, physicians, clinical research staff, and collaborating research partners that made this study possible.
As we have hopefully demonstrated in the past, across conditions as desperate and disparate as MOCD type A and ATTR cardiomyopathy, we recognize now our responsibility to the community that made this work possible and therefore plan to move expeditiously to provide this medicine to patients broadly. Turning to slide five, I'll take a brief moment to provide some corporate context for today's data. As many of you know, BridgeBio Pharma was founded almost 10 years ago to target well-described genetic diseases at their source. Our efficient R&D engine has helped generate almost 20 INDs and three approvals to date, and we hope to add BBP-418 to that list in short order. Today's data represent the first of three major current and upcoming phase three readouts for us, with results from our ADH1 and achondroplasia efforts expected in the near term as well.
Together, these and ongoing earlier stage programs should provide, on a risk-adjusted basis, a reasonable tapestry of impact for the patients we serve and investors alike. Turning back to the program of the moment on slide six, I thought I'd make two final observations that pertain more broadly to our efforts. First, although we deploy many different modalities in an effort to target causal drivers of Mendelian disease, where we can, we often use small molecules. In many of the disease areas in which we play, there's sometimes a misconception that small molecules, while perhaps being more efficient to develop or safer, can't provide the type of efficacy other modalities can.
Here, with perhaps the most impressive data set generated to date in the muscular dystrophy space, we once again show that the quantitative impact on the causal genetic driver is what counts, and that small molecules can provide optimal impact safely and obviously in the most cost-efficient form for society in the long run. Secondly, we were profoundly enthused to observe improvement for the patients in this trial. It's not a new concept, but a good reminder that intervening to take away the biochemical insult can result not only in the halting of ongoing pathology, but indeed in improvement. Reliably improving patient lives is the ultimate aim for any therapeutic we develop, and BBP-418 has met that high bar. With that, I'll turn it over to Christine and team to tell you more about the specifics of this remarkable trial result and the next steps for this program.
Thanks, Neil. First, I'd like to thank our BridgeBio Pharma team who have worked at a high pace with high standards to achieve this milestone. I'd also like to thank the community of collaborators, patients, caregivers, investigators. Without them, this would not be possible. When I speak with patients, I'm first inspired by their courage and struck by their hope for a therapy. Because LGMD2I/R9 is a progressive disease, what they can believe in is something that could stop or slow the progressive loss of daily function. These data show BBP-418 could be transformative in not only slowing the loss, but improving clinical function too. On slide nine, the data are striking in how consistent and how robust it is across all key endpoints measured.
The results were highly statistically significant for glycosylated alpha-dystroglycan at three months, at 12 months, serum creatine kinase at 12 months, and our functional measures, 100 m time test, and forced vital capacity at 12 months. On the next slide, we compare these results to our expectations. Relative to our base case, this was really a home run scenario. We expected robust biomarker changes in glycosylated alpha-dystroglycan and serum creatine kinase, which were demonstrated and exceeded our expectations. We did not expect statistical significance, however, on the functional endpoints. The study wasn't powered for statistical significance on functional endpoints, so the fact that we saw such high statistical significance on 100 m time test and forced vital capacity at 12 months is really quite remarkable. Not only did we see separation from placebo, we saw improvement in the treatment arm.
This is remarkable and the first time that I'm really aware of any therapy demonstrating functional improvement in a randomized controlled study in limb girdle. This underscores the potential for BBP-418 first to market for a disease-modifying therapy for LGMD2I/R9. I will now turn it over to our Chief Medical Officer, Dr. Doug Sproul, to walk through the data.
Thank you, Christine, for that kind introduction. It is a distinct pleasure of mine to have the opportunity to present the top-line phase three FORTIFY interim analysis data. It is a special privilege as a member of this community to be able to present such impressive data. Before I present the data, I would be remiss without expressing the immense appreciation that we have for the patients and their families who have contributed and sacrificed so much to advance care and research in LGMD2I/R9. Particularly call out the tireless work of our patient advocate community partners and the many physicians, clinical trialists, caregivers, clinical research staff, and other collaborating research partners who have all contributed in such a major way to this data and the ongoing advances that we see in the field. Moving to slide 13, FORTIFY is our ongoing randomized placebo-controlled phase three study of BBP-418 versus placebo.
This is a well-controlled and balanced study comparing patients treated with BBP-418 versus placebo in a double-blind randomized controlled manner. Patients are randomized two to one to receive BBP-418 versus placebo. We are reporting the top-line results of our interim analysis that involved the first 72 patients to complete at least one year of clinical study. I'll be discussing our interim endpoints that we have assessed in a formal, statistically rigorous manner. That is including our biomarker glycosylated alpha-dystroglycan, the change from baseline at three months as well as at 12 months. We are also assessing creatine kinase, which is a widely used and well-established marker of muscle injury and breakdown. We are assessing two important and clinically meaningful clinical measures widely used in neuromuscular research. The first is the 100-meter time test, which is an assessment of ambulatory function as well as fatigue.
The second is a broadly used measure of pulmonary function, forced vital capacity. As I've mentioned, this is a double-blind randomized control trial. The placebo and BBP-418 arms were stratified by age, by ambulatory status, as well as by genotype to allow a well-balanced and well-controlled study that I am eager and proud to present today. Before I get into the clinical markers, I wanted to give my colleague Uma Sinha the opportunity to discuss the dramatic results from our alpha-dystroglycan glycosylation bioassay. With that, I'll pass the baton to her to speak.
Thank you, Doug. It's an incredible pleasure and a source of pride to be able to present the biomarker data that the whole team has worked long and hard on. Most importantly, the patient samples, which allowed us to develop the biomarker assay. I'm incredibly grateful for those. First, let me remind everybody about the mechanisms of this disease. LGMD2I/R9 is caused by mutations in FKRP that lead to decreased enzymatic activity of FKRP. This in turn reduces the extent of glycosylation of alpha-DG. Hypoglycosylation of alpha-DG is a core defect in the disease, and this is consistent with the genotype-phenotype association of L276I mutant and other heterozygous FKRP genotypes that are in the literature, and we have also tested in our natural history study.
The hypothesis that we are testing here is that by BBP-418 dosing, we are targeting the disease at its source, restoring glycosylation of alpha-dystroglycan, and thereby enabling the muscle to continue binding laminin at the expected level. We have developed a proprietary validated western blot assay to accurately and reliably measure glycosylated alpha-DG directly in skeletal muscle tissue. This is important on multiple levels. It's a proprietary assay. FDA has reviewed our approach and agreed that it is reasonable. What's novel about this assay? The assay uses two antibodies for immune detection of alpha-DG. One directly measures glycosylated alpha-DG, and the other measures the core protein. It's important to remember that the first antibody is detecting the functional moiety, the moiety responsible for laminin binding. In this slide, we're showing you representative data from phase two. Both glycosylated and non-glycosylated protein is being shown here.
As you can see in the untreated patients, there's barely a signal for the glycosylated alpha-DG protein component. In this data, we have confirmed that upon BBP-418 dosing, already at three months, we are detecting an increase in the glycosylated alpha-DG level, which is sustained at the six-month level. This was the dose-finding phase two data, so it allowed us to build on our hypothesis. Another thing that we have done is use this validated assay to measure baseline levels of glycosylated alpha-DG across our natural history, phase two, and phase three studies. I'm happy to report that the results have been consistent and given us more faith in what the assay is measuring. As Doug has already mentioned, the change from baseline in glycosylated alpha-dystroglycan was the primary endpoint of the phase three trial. We have observed a robust and rapid increase in glycosylated alpha-dystroglycan at three months.
I'd like to focus on the three salient points that this data set is telling us. One is that the change from baseline in alpha-dystroglycan is robust and seen rapidly at the three-month time point, very statistically significant. This increase is sustained through the 12-month period. The third point I'd like to remind everybody about is that our knowledge in the natural history study as to how the baseline levels of glycosylated alpha-dystroglycan behave, that has been confirmed in this study. There was essentially no change in the placebo arm. Our preclinical data in mouse models, as well as in the natural history study, told us that targeting a 5% change in glycosylated alpha-dystroglycan would be expected to be a clinically meaningful benefit in the patient population.
As you can see from this data, we saw an increase of 17% of control at the three-month time point, and the effect was sustained at the 12-month time point with a 23% change from baseline. Target was 5%, so we have definitely exceeded expectations here. I'd like to now turn this over to Doug to delve deeper into the clinical data.
Thank you, Uma, for that fantastic overview of the glycosylated alpha-dystroglycan bioassay. I'd like to build upon those amazing and dramatic results that we're seeing from our bioassay, which shows an approximate doubling in glycosylated alpha-dystroglycan levels amongst patients treated with BBP-418. We're seeing a similarly dramatic, large, statistically significant reduction in serum creatine kinase amongst patients treated with BBP-418, a difference of 82%, a decrease of 82% from baseline at 12 months. This is an amazing observation, just to put it in a little bit of context, a large proportion of patients treated with BBP-418 achieve levels that are within one or two times the upper limit of normal. This suggests a marked reduction in muscle breakdown that's indicated by this reduction in serum creatine kinase. We demonstrated with the bioassay that we have an impact on cellular physiology, that we're improving and increasing glycosylated alpha-dystroglycan levels.
That's translating to a large and important reduction in muscle breakdown that's measured using and demonstrated using serum creatine kinase. These are results that we expected to see, to be perfectly frank. We have confidence in this compound. What is most exciting is what I'm going to talk about in the next few slides, that this physiologic effect, this biologic effect that we're able to demonstrate now, excitingly translates as well to signs and signals of meaningful and important clinical impact. We are excited to present data that is demonstrating that third link in the chain, that we're demonstrating the impact on the physiology that's translating to reduced muscle breakdown. Now we're able to report, excitingly, an impact on clinical function as well. We are observing a 0.27 m/s improvement amongst patients treated with BBP-418 versus placebo in the 100 m time test.
To put a little bit of clinical context, the 100 m time test is a broadly used clinical and clinical research tool to assess ambulatory function and fatigue in patients with neuromuscular diseases. As we have seen in the natural history of the disease and demonstrated in our placebo arm, we see a consistent and inexorable decline in performance on this scale. We see a 0.12 m/s decline in patients treated with placebo. In contrast, we're seeing an improvement in patients treated with BBP-418 in their velocity of performance on the 100 m time test. This translates to an approximately 14 s faster performance amongst patients treated with BBP-418 when compared with patients treated with placebo as far as the time to complete this test. This is a statistically significant result, and it's a clinically meaningful result that we're seeing in patients treated with BBP-418 on their ambulatory function.
Moving to the next slide, we're seeing a similarly dramatic and remarkable and improving performance in pulmonary function in patients treated with BBP-418 versus placebo as well. Amongst patients treated with BBP-418, we see a 3% increase in percent predicted volume from baseline, which represents an approximately 5% increase in percent predicted volume versus placebo. Taking a step back, pulmonary function is a critical system impacted in patients with LGMD2I, has a marked impact on morbidity and mortality. Forced vital capacity is measured in liters, but then adjusted for the gender, height, weight, age of a patient to give a percentage of how they should perform on this test. What we know from the natural history is that we see an inexorable 2% decline and loss year upon year upon year upon year, and that's actually seen in our placebo arm as well.
In contrast, patients treated with BBP-418 have experienced an improvement in pulmonary function, an improvement in forced vital capacity that represents a 5% difference between the percentage predicted volume in one year between patients treated with placebo versus patients treated with BBP-418. This is a broadly clinically meaningful as well as statistically significant result that we're observing in patients treated with BBP-418 in this study. This summarizes, and not to beat a dead horse, but frankly to beat a dead horse, we're seeing not just stability, we're seeing not just a slowing of the reduction in loss compared with placebo, but we're seeing an absolute and statistically significant and clinically meaningful improvement in patients treated with BBP-418, not just with placebo, but also with their baseline status. That's a remarkable and really unprecedented result, particularly in the context of a double-blind randomized clinical trial.
This is the most impressive placebo-controlled data, in my opinion, in the LGMD space by a wide margin, perhaps in the entire muscle disease community to this date. I'm extraordinarily proud and excited to have had the opportunity to present this data to you today. I'm equally proud and happy to report that we have a continued highly favorable safety profile of BBP-418. We have no new or unexpected safety findings that have been observed in our phase three study. These are results that are consistent with our phase two study, consistent with everything that we previously reported. We have a low discontinuation rate overall. It's higher in the placebo group. We have no treatment-related serious TEAEs that have been observed in our phase three study.
The interim analysis continues to support that favorable risk profile as well as what I would consider a much increased benefit profile of the product. We're excited to present these top-line results today. What we've executed on to date sets the stage for an ambitious year and years ahead for our program, and we're extremely excited to move this program forward aggressively into the commercial phase of development. We plan to engage the FDA to discuss our pathway for NDA submission later this year or in early 2026. We intend to present the broader phase three data from our FORTIFY interim analysis results at the Muscular Dystrophy Association Clinical and Scientific Conference in March of 2026.
We furthermore intend to file an NDA with the FDA in the first half of 2026 and anticipate a US approval and commercial launch of BBP-418 to treat patients with LGMD2I/R9, potentially in late 2026 or early 2027. With that, I would like to introduce my colleague Matthew Outten, our Chief Commercial Officer, who will present our overall commercial strategy.
We are very excited about the data discussed today, which set the stage for BridgeBio Pharma's next commercial launch. Over the past 18 months, we've been preparing for this moment, building on the successful launch of Attruby to establish a robust commercial foundation across all functions, including market access, operations, analytics, and marketing. We will now leverage this infrastructure to launch BBP-418, supported by a dedicated field sales team that we have been proactively planning in anticipation of today's results. Our proven launch playbook will enable rapid mobilization for a launch that positions BBP-418 as the standard of care in LGMD2I/R9. We will continue to drive education and awareness as we move toward approval. It's important to remember that today represents the first and only positive data in LGMD2I/R9, a major milestone on our path to approval and for the community that we serve.
We look forward to sharing more about our commercial strategy as we get closer to approval. For today, there are two key takeaways. First, the data are as strong as we could hope for heading into launch. Second, our commercial organization is ready to execute, drawing on the same experienced teams that successfully brought Atrubi to the market. We are poised to do it again with BBP-418. With that, we will now open the discussion and start the Q&A portion of the call.
Thank you. We will now begin the question and answer.
Thanks, everyone, for joining this call. Together with our amazing team, I'm grateful to be able to share with you, on behalf of the extraordinary physicians, patients, families, and caregivers involved, the positive phase three results of our FORTIFY clinical trial for patients with limb girdle muscular dystrophy type 2I/R9. The strongly positive and consistent data the community worked tirelessly to generate come together at this moment to portend a new and better day for current.
If you would like to ask a question, please press *1 on your telephone keypad to raise your hand and join the queue. If you would like to withdraw your question, again, press star one. We also ask that you limit yourself to one question. Your first question comes from Tyler Van Buren with TD Cowen. Please go ahead.
Great. Good morning, guys. Congratulations on the tremendous results. It looks like the results exceeded your home run scenario for the interim. I'm curious just to better understand what you think explains the outperformance. The 5% FVC benefit seems striking. Could you elaborate on the clinical significance of that 5% as well as the 14 s improvement on the functional outcomes? Why would the FDA allow patients to continue on placebo for another two years given these data?
All right. Thanks, Tyler. I don't think that was one question, but we'd love to answer all of them. I'm going to turn it over to our team advisor.
Hi, this is Doug Sproul. I'll address the first question, which was regarding why we saw the results that we did and whether we were surprised by the results. I have personal belief in this compound. Personally, this was my hope and expect hope that we would see this. I believe that this product would have demonstrated this at any point. My biggest concern, frankly, was the endpoints and the ability to demonstrate a material effect over a relatively brief period of time. There are two aspects, I think, that drive how we were approaching the study and explain the outside results. The first is that our study was structured around the concept of stability. It's been reiterated over and over again from the community that just stabilizing the disease, stopping it from getting worse, was an important advance that they would consider a strong win.
Our program was based around that as being kind of the minimal efficacy that would be clinically and important for patients and really a meaningful advance for the field. We also expected and always concern ourselves with the concept of a placebo effect. Anytime you do a study in a placebo-controlled manner, patients perform differently than they might in an otherwise open natural history perspective. Those two aspects were brought into account as we designed and structured this study. While this is an upside scenario, it's something that we hope to be able to demonstrate. It wasn't what we considered necessary. This is gravy on top of the turkey, so to speak. I think that explains why we're seeing it. There's such a much greater difference in placebo versus the clinical improvement that we're seeing on these measures, and that would drive the statistics.
I think the second question was regarding the meaningfulness of these measures, particularly FVC.
FVC, forced vital capacity, is a broad tool used in clinical practice across multiple specialties. FVC has been used as an endpoint in a number of different trials, both intrinsic pulmonary diseases as well as in the neuromuscular community. Depending on the different studies, there are different approaches for what would define clinical meaningfulness in a specific disease. The difference we're seeing at 5% is broadly within and above the ranges that people generally consider as intrinsically meaningful in clinical trials and in clinical practice for this disease, and in clinical practice in general use in specific for this disease. The third question, I can't remember.
The third question was about the ability to continue treating people in the study and the placebo arm. I think on that question, Tyler, I think it's a good question. Obviously, with the strength of this data and the clean safety profile, it's something that we're going to have to align with the FDA on before we can make any, you know, on the optimal path forward before we make any changes.
Your next question comes from the line of Salim Syed with Mizuho. Please go ahead.
Hey, congrats, guys. Thanks for the question. If you don't mind, I'll also ask three questions. I guess the first one here is just on the different subgroups you guys had in this trial, the L276I homozygous patients versus the other FKRP genotypes. Can you maybe just articulate if there was any difference between the two groups, or if you saw more or less benefit in one versus the other? Then just a clarification just on the N that was in the different clinical endpoints here. I think you had like 49 on one, 46. This is all for the drug arm, 40 for like 100 m time test, 35 on forced vital capacity. Can you maybe just clarify why the different N on the different clinical measures at 12 months? Lastly, if you think this mechanism could be used in other LGMD subtypes. Thanks.
Okay. Thanks, Salim. Uma, you want to take the first part of that question?
Sure. As you could see when Doug showed the study design, we had a very broad enrollment criteria for the phase three trial. It included both the homozygous L276I patients, and that's about 75% of the study population representing what we see in real-world evidence. The other 25% were the heterozygous and the other FKRP genotypes. We have seen very robust and highly statistically significant results in both of these genotype segments. This is quite consistent with BBP-418 to be a disease-modifying therapy, an oral disease-modifying therapy with a potentially very broad inclusive label. As you can tell, this data is very new to us, so we're analyzing all subgroups and getting clarity on what the data means. Again, very, very promising, highly statistically significant data. Additional details as they emerge, we're going to be presenting it in future medical meetings.
I'll turn it over to Doug to answer the question.
The second question was why do we see different Ns on some of the different endpoints? The quick answer for that is that the data incorporates the available data. In the case of the 100 m time test, there are some individuals who are unable to perform the test and are therefore not incorporated into the analysis. For forced vital capacity, our collaborators applied a rigorous standard to ensure validity of the test and the assessments. There were certain patients who were excluded based on their inability to perform the test correctly. This is incorporated into the test statistic, and the test statistic that we are reporting is a conservative adjustment to reflect that.
Yeah. The other part about it, Salim, is just the enrollment rate. For example, the primary endpoint of glycosylated alpha-dystroglycan at three months looks at all the patients available at three months, but then, of course, not all of them made it to the 12-month time point at the same time to collect those data. I think your last question was about the applicability of 418 in other LGMDs. We do believe that it could be applicable for LGMD2M and 2U in the US and Europe. These are a little bit smaller conditions than 2I. In Japan, it may have potential in Tokiyama. That's a muscular dystrophy that is actually kind of a found mutation in Japan. It's specific to Japan, but actually the second most common form of muscular dystrophy in Japan. Those are probably the most likely mutation expansion opportunities for 418 specifically.
Your next question comes from the line of Corey Kasimov with Evercore ISI. Please go ahead.
Hey, good morning, guys. Thank you for taking my question and great to see such strong data. I wanted to ask more about the commercial opportunity. I'm curious, at this point, what percentage of patients are diagnosed today, both in if you can split it between like in the US and globally? From a strategic standpoint, do you plan to commercialize 418 yourself outside of the US, or would you look to out-license the molecule? Thank you.
Thanks. I'm going to turn it over to Matt.
Hi, Corey. Thanks for the question. First, we plan to launch ourselves globally, and we've been preparing in anticipation of positive data. Those assumptions that we put into that include about 7,000 patients between the U.S. and Europe, and about 2,000- 2,500 of those are in the U.S. Just to give a little bit of color on some of the commercial parameters that we're looking at, we'll start to refine our pricing assumptions, things like that. As you're thinking about what to expect, I would expect sort of normal rare disease pricing similar to other recent rare disease launches. We'll be using the current infrastructure that we have to kind of put all this together. It should be another blockbuster drug for BridgeBio Pharma.
Yeah. I think I would add just on the diagnosis rates, it's a little TBD right now since there's nothing available for these patients right now. There's no therapies. We must be the first to market for, you know, disease-modifying therapy. I will say I think there's some tailwinds already that exist in the market. There is sponsored genetic testing that's available, for example. I guess, you know, anecdotally, our experience with the clinical trial enrollment may suggest that there's actually kind of maybe more patients identified than we thought. I mean, with the clinical trial enrollment, we enrolled it eight months faster than expected and 20% more patients than expected. The demand for treatment and to be in a study there, again, suggests that there might already be a large volume of patients identified.
Your next question comes from the line of Mani Foroohar with Leerink Partners. Please go ahead.
Hey, guys. I'd like to add my congratulations on the data. I have a quick question about correlation between glycosylated alpha-dystroglycan and the various functional measures. Can you share with us to what extent we could get a little bit of a sense of the correlation between one and the other, recognizing you're limited to what you've already disclosed? Where might we look to see a more sort of detailed disclosure of how the one correlates with the other?
Yeah. Thanks, Manny. That is going to be part of the ongoing analysis. This is really only that top-line data. We're going to use that data to have a discussion with the FDA, and we'll present a fuller data package most likely at the NDA in March.
Your next question comes from the line of Josh Schimmer with Cantor. Please go ahead.
Hey, congrats on the data, and thanks for taking the questions. Maybe just clarifying for the U.S. patient population, you'd said 2,000- 2,500 patients. Are those all identified? How did you kind of come up with that estimate, especially because you suggested it potentially could be higher? Thank you.
Right. The question was about just how we came up with our patient number estimates. I think that's the question. The estimates are derived from basically the prevalence in the Northern European population. This is a disease that has a founding mutation in Northern Europeans, so the prevalence is much higher in Northern European countries and places where Northern Europeans immigrated to. If you take those prevalence rates and extrapolate them out to the broader population, that's what we've come up with for our patient population.
Your next question comes from the line of Biren Amin with Piper Sandler. Please go ahead.
Yeah. Hi, guys. Thanks for taking my questions and congrats on the data. I guess, you know, given the strength of the results on the clinical functional endpoint, and you talk about NDA filing in first half 2026, do you still plan to pursue the accelerated approval pathway, or is there a path to full approval? Maybe second question on, you know, a path for ex-US approval. Would you pursue approval prior to readout of the full analysis? I guess, you know, third question is, when can we expect the final full analysis from the trial?
Yeah. Thanks for the question. I think it's a good question. Obviously, given the strength of the data, the improvement on the functional endpoints, and the clean safety profile, it is the key question that we want to align with on the FDA about whether to seek an accelerated approval, which is our original strategy, or if this data, as we think, supports a full approval in the U.S. In Europe, we are also going to align with the European regulatory agencies on a path forward there. I think the key principle for us is, given the strength of this data, how do we accelerate access for patients as quickly as possible?
Your next question comes from the line of Andrew Tsai with Jefferies. Please go ahead.
Hey, good morning. Thanks for taking my question. Congrats also on the compelling data set. Aside from the FDA meeting that you have, what gating items, if there are any, are still outstanding before you can file the NDA? Do you need to run any other peripheral studies in the meantime, or do you even have enough drug for a commercial launch? Secondly, does it make sense to file for breakthrough designation? Thank you.
Yeah. The gating item really is this alignment with the FDA on whether we're seeking accelerated approval or whether we're seeking traditional approval. You know, we don't anticipate that that's going to affect our timelines. We still anticipate filing our NDA in the first half of next year. We already have priority review. We also have the rare pediatric designation on this program as well. At this point, I don't think that filing for breakthrough is going to give us any additional benefit.
Your next question comes from the line of Danielle Brill with Truist. Please go ahead.
Hi, guys. Good morning. Thanks so much for the question and congrats on the excellent data. I have a few questions. First, I'm just curious, maybe you can walk us through how you selected the 100-meter time test and forced vital capacity as the functional endpoint measures for the 12-month analysis. Is there something specific about these that would make them more sensitive to a change after 12 months than, say, NSAID or a 10 m walk test? Were the changes observed in the placebo arm on 100 m time test and serum creatine kinase levels also consistent with natural history? Maybe just a clarification. In your prior conversations with the agency, were they generally supportive of a potential full approval filing with 12 month data that showed significant improvements on functional benefits? Thank you.
Thanks for the question. Doug, do you want to take the clinical question?
I'll take the clinical questions, and then I'll kick it back to Christine for the regulatory question. The first question is why those endpoints and how is that different from the other potential endpoints that you might excel? We selected specifically the 100 m time test and FVC because of the expectation that these were two endpoints that would be likely to be able to show relatively early association and improvement with following administration of the therapy. The 100 m time test is the, I would call it the modern version of the six-minute walk test, the measure of ambulatory function and fatigue that is highly sensitive to changes in function and ability that shows a better ability to differentiate decline in higher functioning patients than the 10 m walk test. We felt that this is a more sensitive scale than the other ambulatory measure.
FVC has been well established by the history of the disease to show pretty outsized decline. The 2% decline that we see in the placebo arm mirrors what we see in the published natural histories, and that's a pretty stark year-upon-year-upon-year decline. This was specifically chosen because of the decline that we expected to see in the untreated patient. What we're demonstrating today, though, is not just an avoidance of that decline, but a pretty marked improvement in the overall function in those two measures. With regard to the regulatory question.
Yeah. I'll take the regulatory question. Maybe just to back up, the way we designed the study was really in alignment with the FDA, which is the primary endpoint was the North Star endpoint at 36 months. That was the endpoint that the FDA strongly encouraged us to use for approval. Given that, you know, that incident is a relatively insensitive one, takes a long time to show treatment benefit, that's why we wound up with the study with the interim analysis at 12 months where the primary endpoint was based on glycosylated alpha-dystroglycan. The strategy was to seek accelerated approval based on the biomarkers, based on the fact that they are the cause of this disease, and we're targeting the disease at its source and directly impacting glycosylated alpha-dystroglycan.
Our prior discussions with the FDA have all been about accelerated approval on, and the, I guess, the potential to use glycosylated alpha-dystroglycan as the surrogate. We weren't really expecting statistical significance on the functional improvement at 12 months, and that really wasn't, you know, the tenor of our prior discussion. Given that we have seen highly statistical significant functional improvement, as well as a clean safety profile, which we did expect, I think that's where we want to reopen discussions with the FDA.
Your next question comes from the line of Anupam Rama with JP Morgan. Please go ahead.
Hey, guys. Thanks so much for taking the question and congrats on the data. Christine, maybe I can follow up on your just prior comment. Anything more you can share on the nature and severity of some of the treatment emergent adverse events you saw in the treated group? Also, can you say anything about the baseline characteristics and the severity of the patients enrolled in the study just to help us further kind of put the efficacy that we're seeing into context? Thanks so much.
Yeah. Thanks for that, Anupum. I think on the treatment emergent events, we aren't sharing a lot of detail right now only because we need to be mindful of the integrity of the ongoing study before we have the discussions with the FDA. What we've said, of course, is that there are no new ones that we've identified and that the safety profile is very consistent with phase two. I don't know, Doug, if you want to add any more color to that in terms of what we've hoped to discuss about.
It's unfortunately a tricky question because the numbers are very low, and we want to avoid further impacting study integrity. There were no new TEAEs, certainly nothing associated with therapy. The safety and risk profile has not changed from what we've described previously.
Yeah. Encouragingly, as you said as well, the attenuation rate was very low, and it was higher in the placebo arm. I think in terms of the baseline characteristics for the phase three, it's very consistent, actually, with our phase two study population. I don't know if that's anything else.
Yeah. I mean, it's a mixed cohort, and we'll be presenting additional, we'll continue to present this in greater details moving forward. There's a mixed cohort of patients with homozygosity for L276I and patients with other FKRP genotypes that roughly matches the general population. The predominance were ambulatory patients because of the structure of this study. There were a sizable cohort of non-ambulatory patients enrolled as well that are incorporated in appropriate analyses, including forced vital capacity. This is a broad study that we believe will provide sufficient coverage for a relatively expansive label.
Your next question comes from the line of Paul Toy with Goldman Sachs. Please go ahead.
Hi. Good morning. Congratulations on the data, and thanks for taking our questions. My first question is, can you maybe comment on if the magnitude of benefit was the same in pediatric patients as it was in the adult patients just in the context of the natural history? I think your international enrollment was largely limited to adults, so maybe just some clarity on that would be helpful. My second question is, as sort of a first-in-class for this therapy, do you anticipate a potential FDA adcom might be held for this, just given the novelty of the category and just sort of the unknown treatment options for this particular disease? Thanks for taking our questions, and congrats again on the data.
Thank you. On the pediatric subgroups, all the subgroup analyses are ongoing, so we'll disclose that at a later time. On the, sorry, what was the second part of the question? Adcom, right. Adcom. Prior to this data, I actually thought an adcom was more likely than not, and now I think it's the opposite. I think given the strength of the data, how robust it is, how consistent it is, how overwhelming and positive it is in the clean safety profile, I'm not really sure that there's, I don't know what we're going to discuss. I think it's less likely now.
Your next question comes from the line of Jason Zemansky with Bank of America. Please go ahead.
Good morning. Congrats on the data, and thanks for squeezing us in. I wanted to ask on your expectations over the long-term outcomes. I mean, granted, things are still early, but it did appear that the alpha-DG levels continued to improve somewhat over the 12 month interval. Is there the potential that longer-term exposure can drive even better responses? Alternatively, is there a limit to how much you can replace and at some level, you know, patients will decline at, you know, albeit a more modest level? Thank you.
Yeah, thanks. I'll turn it over to Doug.
Yeah. Obviously, we'll need to see ultimately. Our expectation, based on what we've seen from our natural history, from the natural history studies, what we've seen from the longer-term datasets from the University of Iowa, is that patients who are not treated will experience a continued ongoing and inexorable decline along the fashion that we're seeing in our placebo arm, and that will continue in the longer term. We believe that this demonstrates a change in trajectory. You know, the magnitude of that and, you know, the continued directionality obviously will remain to be seen. We expect that that gap and that difference between the treatment and placebo arms will continue to grow with longer and longer therapy. Again, that remains to be demonstrated with the data.
One more thing, which is the data that we showed, that's the change from baseline. The one-year time point, we're essentially already doubled the baseline level of glycosylated alpha-DG. About 21%- 22% has already increased by 23%. It's a remarkable increase already at 12 months.
Yeah, just with that in context, what we believed was clinically meaningful was an absolute increase of 5%. The fact that we're getting a 17% increase already at three months is pretty meaningful.
That concludes our question and answer session. I will turn the conference back over to Christine Siu for closing comments.
All right. Thanks, everyone. I think, you know, based on the strength of the data, I think we're very excited about the potential here. It just could be very transformative for these patients, for this community, because we could offer really, you know, we could be first to market with an oral disease-modifying therapy. It's a functional improvement. We're excited. Thank you.
Ladies and gentlemen, that does conclude today's conference call. Thank you for your participation, and you may now disconnect.