BridgeBio Pharma, Inc. (BBIO) Earnings Call Transcript & Summary

Good day, and thank you for standing by. Welcome to today's discussion with BridgeBio, which will cover the company's novel bioassay, updates on Phase II data and the Phase III trial design for BBP-418 in Limb-girdle Muscular Dystrophy Type 2i, known as LGMD2i. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to introduce your speakers for today, Dr. Jeffrey Rosenfeld, MD, PhD, a specialist in neuromuscular medicine and Professor of Neurology at Loma Linda University School of Medicine; Dr. Douglas Sproule, CMO of Bridge Bio's LGMD2i program; and Christine Siu, CEO of BridgeBio's LGMD2i program. I will now hand it over to Neil Kumar, CEO.

All right. Thank you, operator, and thanks, everyone, for taking the time to join us this morning. As a brief reminder, and as noted on Slide 2, we will be making forward-looking statements today. Please refer to our filings with the SEC for further information. All right. We're collected this morning to review the latest data associated with our first-in-class program in Limb-girdle Muscular Dystrophy Type 2i. Before getting into the slides, I'll make a few framing comments. Since our last update, this program has taken several important strides forward for the patients we are attempting to serve. First, we have developed a high fidelity bioassay that quantitatively measures the key molecular insult associated with this well-described condition by cost inflation levels of the alpha-dystroglycan complex, which I'll refer to going forward as ADG in my comments. Using both natural history and Phase II data, we've asked and answered key questions regarding the linearity of ADG glycosylations measure and the appropriate normalization of the signal in the context of changing total protein levels. Second, using this refined bioassay in concert with our large and ongoing natural history study, the team has established decreased ADG glycosylation as correlated with ever-increasing disease severity. The less you have, the more severe the disease is. This genotype-phenotype correlation coupled with the fact that this condition is uniformly driven by loss of function mutations in FKRP, an enzyme responsible for ADG glycosylation, argues strongly for the usefulness of this measure in the preliminary assessment of therapeutic efficacy. Third, using this novel bioassay and now updated time points, we demonstrate the approximate doubling of ADG glycosylation levels in both compound heterozygous and homozygous recessive patients. This couples well with improvements across other measures, including CK. Fourth, and perhaps most heartedly -- hearteningly, despite it being open label data, of course, we show improvement in 15 months in key ambulatory and clinical measures for patients on an ongoing Phase II study. Finally, the team will walk through our current Phase III thinking and design, which seeks the ability to gain approval on ADG glycosylation given the points made above and coupled with the safe profile of this drug to date and the severity of the unmet need. Importantly, however, the trial will employ a nested trial design that seeks to establish efficacy on longer term -- in the longer term against a broader set of functional end points. Okay. From here forward, I'll keep my comments brief as I'm privileged to be joined, as the operator mentioned, by our own internal leadership team, including Christine Siu, Dr. Doug Sproule; Dr. Anna Wade, and one of the real leading experts in this field, Dr. Jeffrey Rosenfeld, who's been a guiding light to us and a true champion for patients suffering with LGMD2i. I'll refer to slide numbers as I walk through the first couple of slides here, building on the last comment and moving into the slide deck. On Slide 3, I'll just take a brief moment to thank all the physicians, researchers, patients, families and advocates associated with these studies. This effort, as many of you know, in particular, literally started with effective families and a small number of passionate researchers. We're lucky to partner with them as ever, and we depend on the community's efforts, past and present. Okay. Moving to Slide 4. As you can see, this is a large unmet when measured either by the number of patients affected by this condition or the severity with which they are affected, which in turn suggests the lack of effective standard of care. Some 7,000 patients between the U.S. and EU are affected, we think, seemingly the most common Limb-girdle Muscular Dystrophy that we know of and an additional 2,000 patients may be afflicted by related conditions. But constellation, as many of you know, of alpha-dystroglycan is regulated by 3 enzymes that each use sugar ribitol as a common substrate. The other 2 outside of FKRP, which is mutated in LGMD2i, being ISPD and FKTN. Our approach could in theory work for all 3 contexts, but we've only tested in LGMD2i to date. Turning to Slide 5, you can see here the design criteria we contemplated when attempting to make this first-in-class therapy. We wanted to create a disease-modifying therapy that targeted this well-described disease at its source. We hope to do so safely and, importantly, to contemplate an approach that would not suffer from overdosing the gene or the FKRP enzyme. And finally, we wanted to create a convenient oral medicine. Moving to Slide 6. I'll just briefly put this exciting program in the context of our late stage pipeline here at BridgeBio. When this program moves into Phase III later this year, it will join another 3 programs in Phase III, including our efforts in ATTR cardiomyopathy, achondroplasia and ADH1. All conditions with large unmet need. Okay. Let's focus back on the condition and data at hand. I'm privileged to turn this call over to Dr. Jeffrey Rosenfeld. Dr. Rosenfeld is a professor and Associate Chairman at the Department of Neurology and the Director of the Center of Restorative Neurology at Loma Linda University Health Systems. His clinical activities over the past quarter century plus is largely focused on the development of unique multidisciplinary treatments for muscular dystrophies, such as LGMD2i, motor neuron diseases and a variety of other progressive neuromuscular conditions. Dr. Rosenfeld, thanks for joining us, and I'll pass it over to you at this time.

Thank you very much, and good morning, everyone. Can I see the next slide, please? So I'd like to speak for a moment about the field of Limb-girdle dystrophy because, in my perspective, this has been a very interesting and exciting evolution just over the past 25 years or so, and I was in practice for that whole time. When I started out, Limb-girdle dystrophy was more of a description of what you saw at the clinic, but you couldn't actually tell what type of Limb-girdle dystrophy it was. And then over 10 years from 2000 or a little bit before that until 2010, there was almost an explosion of subtypes of Limb-girdle dystrophy. And these were largely defined by individual protein mutations. So whereas we used to call this collectively our waste faster diagnosis means if you didn't know what it was and the clinical picture fit, you would just say the person had a type of Limb-girdle dystrophy, now that wasn't sufficient anymore. And for the past, perhaps, 10 to 15 years, it's not been sufficient. You have to say what type, and that type is defined by particular mutations. And so we actually -- that explosion was so significant, we would have letters to designate the different forms of dystrophy and so the nomenclature changed just recently to a different naming paradigm so that we could account for more of these subtypes. Well, today, what we're going to talk about is what I consider to be the next generation in this exciting evolution because now at least this type -- one of these types, the Limb-girdle 2i Type now has a potential therapy or treatment. So we've gone one more step past the individual descriptions by the mutations now are actually going to ameliorate and hopefully treat patients with this condition. Next slide, please. Thank you. So as you already heard, the prevalence in the U.S. is estimated at 7,000, although frankly, that -- my estimate might be underestimating it because we have a stream as many patients, now that there could be potentially a treatment, there might be -- in my clinic setting where patients that are now worth the second look to see. And the disability of a patient with Limb-girdle 2i is not subtle. It's a little delayed, you'll see in the subsequent slide, but loss of ambulation in early life, late childhood, early teens, respiratory decline is not uncommon, and cardiac dysfunction is quite common. So by adulthood, this is a fairly pervasive disability. We're now on Slide 10. And as you can see, the -- by comparison to other types of FKRP mutations, there is a bit of a dispensation here. The onset of the homozygote 276, my patient is a little bit later onset of 18 years of age, starts out usually with weakness. The patients that I've seen will have difficulty learning in late childhood or perhaps some falls. But by early adulthood and mid-adulthood, loss of ambulation is very common, respiratory decline. Many of these people are on non-invasive positive pressure ventilation. And as you heard before, cardiac dysfunction is fairly common. So having a therapy to ameliorate this, especially as these patients are coming to attention is -- with greater disability is really an exciting prospect from a clinical perspective. So now I'll turn this back over to Dr. Sproule.

Right. Thank you. And it's certainly my pleasure to have the opportunity to run through our clinical program and highlight some of the exciting early results from our program to date. Neil went through a number of the overview, but I wanted to kind of reiterate a couple of critical points. As Dr. Rosenfeld noted, LGMD2i is a genetically defined disease caused by [indiscernible] mutation of the FKRP gene. FKRP is an enzyme that's critically needed by consolation of alpha-dystroglycan. Dysfunctional FKRP results in hypoglycosylated alpha-dystroglycan, which in turn leads to muscle membrane instability and resulting dystrophic changes in muscle. That's the underlying core pathology of the disease. And as Neil mentioned, we've developed a novel and validated bioassay to quantify glycosylated alpha-dystroglycan, which allows us to directly measure the underlying pathophysiology of the disease and its severity and potentially response to a potential disease-modifying therapy. That will show how glycosylated alpha-dystroglycan levels are consistent with that established patterns of clinical severity seen in patients with different genotypes. So the L276I homozygotes genotype versus patients with other typically more severe genotypes. And I will also talk through, as Neil mentioned, our early clinical data that we're seeing from our Phase II study. And in contrast to the expected decline in clinical function that's seen over intervals of a year or more in untreated population going to show our early Phase II results would suggest improvement in not just glycosylated out for dystroglycan, but also other laboratory market, such as creatine kinase and clinical measures after 15 months of treatment with BBP-418. If you can go to Slide 13, so this schema outlines both the pathophysiology as well as the therapeutic mechanism that -- post-therapeutic mechanism of action of BBP-418. So, BBP-418 is a sympathized version of endogenous ribitol, provided in a powdered form, dissolved in water, taken orally. On the left side of the figure, we see what happens in the untreated disease state. So we have partial loss of function mutations in FKRP, and this results in widespread dysfunctional hypo-glycosylated alpha-dystroglycan in myocytes. And so this insufficient glycosylated alpha-dystroglycan results in susceptibility and chronic susceptibility to injury and, ultimately, all the dystrophic changes that will occur in a Limb-girdle Muscular Dystrophy. On the right side, we see the proposed therapeutic mechanism. So while the FKRP enzyme is deficient and dysfunctional, there's still some residual enzyme activity, it's obligatory for life. So providing supraphysiological levels of the substrate for that enzyme, you can harness that residual FKRP enzyme activity, drive increased full-length functional glycosylated alpha-dystroglycan. If you go to Slide 14. So as Neil mentioned, ML Bio has developed a novel, validated bioassay that measure glycosylated alpha-dystroglycan that can quantify differences associated with FKRP status as well as BBP-418 treatment in this Western blot-based assay uses muscle tissue obtained from the tibialis anterior muscle. It has been validated for use in the clinic as sensitive, specific and robust measure of glycosylated alpha-dystroglycan and the variance across all blocks in each of the studies is under 20%, which is very good from our perspective. If you can go to Slide 15. So this slide shows an example of the bioassay output as applied to patients in the Phase II study and shows how we can measure a potential response to therapy in LGMD2i. On the left column is the Western blot, a run from a pretreatment baseline sample. So what you can see or not see is, there's very little glycosylated alpha-dystroglycan, which is reflected in that -- those yellow bands across the top. Most of the species of direction measuring are that -- that are seen in green signaling lower are non or hypoglycosylated alpha-dystroglycan species. So in contrast, with -- following BBP-418 treatment, we see an increase in that yellow band, that's the fully glycosylated alpha-dystroglycan. And that middle column is after 3 months, the right column is after 6 months of treatment and appreciates the increasingly bright signal, which reflects increased glycosylated alpha-dystroglycan in those -- in the muscle tissue samples. If you move to Slide 17.

Can I make a comment?

Oh, yes, please.

Can you go back to that slide, I just want to make a comment because, for me, this is personally, the most exciting part about this program. To call this a bioassay is perhaps only because we don't have a better word. But most bioassays reflect something that's going on in the disease state. That would be the case of CPK for a lot of muscle diseases. This is more than that. This is an assay that is actually measuring the disease. The disease is impaired glycosylation. And this assay is measuring glycosylation. So if you will, it doesn't get better than that with regard to diseased activity. So I wish we had -- I wish I had this kind of direct readout of disease activity with many of the other diseases that I treat. But that really got my attention when I was first being oriented to the program. So I just want to emphasize that we call it bioassay, perhaps it's a disease assay, it's a better way to put it. But it's for lack of a better word, this is a very direct readout on the underlying pathophysiology of this condition. Sorry for the interruption. I was sharing my perspective on what...

Absolutely. so moving to Slide 16. This is a schematic kind of outlays or outlines are ongoing and completed clinical program. So we've completed 1 natural history study. We have a Phase II study that's ongoing, and we're about to start our Phase III study. So the MLB-01-001 is a 12-month non-interventional natural history study that is intended to provide longitudinal assessment that would be done in a conventional clinical trial to provide a really robust data comparison with our ongoing studies. It also provided an opportunity to obtain serial muscle biopsy samples to establish the framework and validation of our glycosylated alpha-dystroglycan bioassay. I would also say it also provides a framework as far as institutions and patients for lack of a better term, that we expect to be a significant reservoir as we move for enrollment as we move into our Phase II study. MLB-01-003 study is our Phase II study. It is an open-label ascending dose study of BBP-418 in patients with LGMD2i. And I'll talk more about MLB-01-005, which is our Phase III, which will be a large multicenter, multinational double-blind and randomized, controlled study of BBP-418 in patients with LGMD2i. We'll get back into that more. Moving to Slide 17. This shows natural history data specific to our bioassay. Just to remind everyone, as Dr. Rosenfeld pointed out, what we know from the well-established natural history that there's 2 distinctly different populations from a clinical severity standpoint. Patients who are homozygous for the L276I mutation, the so-called common or by gene mutation tend to present somewhat later and have a less rapidly progressive disease course when compared with patients with other genotypes. Typically, one L276I mutation and one more severe, uncommon, but pathogenic mutation. And so as we would expect, based on those established differences in population between the less severe L276I homozygous and it could be more severe phenotype seen amongst patients with other genotypes. We see this when we look at bioassay as well. And the L276I homozygous patients show a less severe reduction in glycosylated alpha-dystroglycan, approximately 11% of what we would expect from normal tissue -- normal controlled tissues versus approximately 5% in patients with other genotypes, when compared with healthy control tissues. As you can see, it's profoundly reduced across all patients compared with what one would expect to see in healthy patients. So this -- moving to Slide 18. This is the schema for the -- our ongoing Phase II study. And this MLB-01-003 study is an ongoing open-label single-site dose-escalation Phase II study involving 14 patients. In addition to safety, efficacy measures, including the NSAD, 100-meter timed test, 10-meter walk test, FVC, PUL2.0, we're also tested longitudinally. And obviously, we measured longitudinally glycosylated alpha-dystroglycan levels based on [indiscernible] biopsy, as we described and creatine kinase and other measures. This is a broad study and enrolled ambulatory, nonambulatory patients, enrolled patients with L276I homozygous and non-L276I homozygous genotype. So it's a small study, but it's a very broad heterogeneous population that provide a pretty reasonable encapsulation of the patient population. If you go to the next slide. This is a safety profile to the state. We're obviously -- this is early on, and there's a lot of work to do, and we're going to continue to monitor safety very closely as would be appropriated with any program. But we're extremely reassured by safety profile that we've seen to date. We've seen 14 possibly or probably related adverse events. They've all been for the most part GI related. These include diarrhea, dehydration, nausea, vomiting, dyspepsia, gastroenteritis and headaches. They were all Grade 1 or Grade 2 in severity, self-limited and not ongoing. No discontinuations or interruptions and therapy have been required. There have been 3 severe adverse events that have been all completely unrelated to this therapy and reflect the severity of the underlying condition. So if you can go to Slide 20, and this is, I think, where we get most excited -- personally get most excited about the results that we're seeing. And again, this is a small study. There's only 14 patients. What we're seeing is the impact of treatment with BBP-418 on alpha-dystroglycan glycosylation on the left. The dark spots in forest green are the L276I homozygous patients. And the -- and what you're seeing there is an increase from a baseline median of approximately 17% to a median of over 40% by month 15. So it's more than doubling that we're seeing glycosylation -- alpha-dystroglycan levels in the L276I homozygous patients. In patients with other genotypes, they're much more severely affected. They're starting at a median of around 6%. We're seeing an increase to a median of around 10%, which is not quite but close to approximately doubling in that population as well. That's obviously a very marked increase relative to the baseline. And certainly, you can talk more about it, but it's certainly an extremely intriguing result. And on the right, we're seeing the impact of BBP-418 on creatine kinase. Creatine kinase is a widely used marker of muscle injury and muscle breakdown. It is a nonspecific marker for this disease and many others. That said, we're seeing a decrease of more than 75% from baseline that's sustained on repeated measures and seen across all patients in our ongoing study. Dr. Rosenfeld, If you have any comments on that?

No, I think this actually reflects the point I was making earlier that CPK, as in the right panel here, is a reflection of disease as it shows the downstream effects of muscle breakdown, whereas glycosylation is the disease. And so, of course, they're going to correlate because one is reflecting the other, but like the alpha-DG assay is so much more to the point of it. So I share here enthusiasm for this slide. It really highlights the novelty and the impact of this program.

Looking good. Slide 21. What we're also very excited to see is that we're starting to see evidence emerge that treatment with BBP-418 may have impact on clinical measures as well. And as is typically seen in many other neuromuscular diseases, you expect that it actually takes time for an intervention to work at the level of the cell, the work that translates to impact on the organ and, ultimately, clinical function. And again, while the study is small, it's open label, it's uncontrolled. We see an increase in velocity on the 10-meter walk test that's depicted on the left. We see a decrease in the time to complete the 100-meter timed test, which is in the middle box. And on the right, we're seeing an increase in the NSAD score, all from -- increases from baseline in the Phase II patients, and that's what is shown within the red baseline. For comparison, depicted in blue is the 12-month trajectory performance seen amongst patients in the MLB-01-001 natural history study, untreated patients. So that's the expectation of what would happen over the population as a rough comparison between these 2 groups. If you go to Slide 22. We're very excited. And to me, the data we see from the Phase II just really creates a ground swung enthusiasm, at least internally and hopefully externally as well to move this program forward in the next stage of development. And we're very excited to announce, as we did yesterday. Our plans for our Phase III trial, which are expected to start this summer. And this will be a 2:1 randomized, placebo-controlled, double-blind study of BBP-418 in 80 to 100 patients with LGMD2i. So the full study will involve 36 months of treatment with NSAD as the primary endpoint. We do plan to conduct an interim analysis. It's a time that approximately 40 patients have completed at least 12 months of follow-up. And that, to me, focused upon change in glycosylated alpha-dystroglycan with the data will be just as robust as we've already seen in our Phase II study supported by selected clinical endpoints and other laboratory markets. We're discussing strategy for accelerated approval with the regulatory agencies, and we'll disclose more in the future as those conversations mature and move along. So I believe that's the end of our discussion. Neil, I guess I'll pass it back to you or Christine, I don't know who will moderate.

I will moderate, yes.

All right. Well, thanks, everyone, for your comments. We'll move into Q&A at this point. I'll turn it over to Christine Siu to moderate that session.

[Operator Instructions] Our first question comes from the line of Salim Syed with Mizuho.

This is [indiscernible] for Salim. I was wondering about the feasibility of the developed bioassay. I mean is there any limiting factor that may preclude doing it, like how much tissue do you need? I mean is the tissue sampling a problem for patients? And also, if you could comment on the potential of using this bioassay as a surrogate for approval? Like would be enough for approval or functional assays are going to be always needed?

Maybe I'll turn it over to Doug to answer the initial question and then wait for a minute.

Yes. So the first question was related to the feasibility and how it's actually performed in patients and whether there's limitations here. This is a needle-based biopsy. So we use a small-bore needle to obtain typically 3 or 4 passes using a landmark-guided approach in the tibialis anterior muscle. The reason that we use that muscle is the easy accessibility and reliability using a needle-based approach. This is very different than an open biopsy that would be performed and from a scientific perspective, frankly, preferable, that would be much more invasive and involved on patients. We've performed in the natural history study. There were 3 biopsies scheduled and performed on patients and patient is generally well tolerated, and we don't expect that there's any limitation to having these procedures performed in properly educated patients as part of an ongoing interventional study.

Yes. And then maybe I'll just take the last part of your question, which was about using the assay as a basis for a surrogate endpoint. That's clearly part of our strategy here, given the high conviction we have in this therapeutic hypothesis. You've heard the excitement around the use of this assay and the fact that it is really directly measuring the cause of the disease, and we're obviously designing the therapeutic to -- around that whole hypothesis. We do have a series of interactions plans with the FDA and other regulatory agencies to discuss a potential to use a surrogate endpoint and we'll have more to say, obviously, later as we have those discussions. But it is something we have high conviction around in part of our strategy.

Our next question comes from the line of Mani Foroohar with SVB Securities.

You talked about your engagement in regulatory authorities. Where are we in terms of nailing down regulatory feedback in FDA minutes, et cetera, around what would be an approvable profile at the interim analysis? Have you explicitly got feedback around what you need to show on -- on bio -- on the assay data, what you need to show on clinical endpoints? Or is that still an ongoing discussion? And how does that inform your conduct that the studies are designed of the Phase III, obviously?

Yes. Thanks, Mani. So I'll kick off with the answer to this question, and then I'll turn it over to Doug if there any other comments. So we've already had a lot of discussions with the FDA on designing the pivotal study. Not just the FDA, but other regulatory agencies as well. And so we have a high confidence in the primary endpoint we're using here for the whole basis of the study. In terms of the interim assessment, that, of course, is ongoing discussion subject to, right, whether the accelerated approval pathway could be open to us. So we don't have a lot more details to disclose at this time as we're kind of in the middle of those discussions, but we can comment on that later. I don't know, Doug, if you have anything to add?

No, I think that generally covers it.

Our next question comes from the line of Tyler Van Buren with Cowen.

This is Tara on for Tyler. So we're wondering if it's possible to file on an accelerated basis in the Phase III based on improvements in the biomarkers, like the ADG or CK earlier than 36 months, perhaps even 6 months based on what you saw in with your bioassay at that time? Or if you think you'll have to wait 12 to 18 months for a functional endpoint confirmation?

Yes, I can kick this off and I'll turn it over to Doug later. I mean, I think that's certainly a good question. I think we have looked at the data and also wonder that ourselves. If you look at the data, clearly, you can see mass improvement in the biomarkers at 3 months. And so the way we've designed this interim analysis, however, is to take advantage of that magnitude right of change at 3 months, but then also to look at trying to correlate it to functional improvement at 12 months, right? So trying to get out of this are the biomarkers reasonably likely to projected clinical benefit. And so that's kind of some of the principles behind how we've designed the interim assessment. Again, right, we have high conviction in that strategy, but that is also subject to our discussions with the FDA and other regulatory agencies. Doug over to you.

Yes. I mean there's -- we have -- the broader study design is built upon relatively conservative assumptions, right? The idea that this is a therapy that has such a good safety profile. There's such an unmet need. What we hear from patients is just stability to keep me from getting worse, that would be a huge win. And we believe if this product could do more. But at the same time, that's all it did, it's a major advance for the community. And so our pivotal -- the full study sort of build out conservative premises around placebo effect around magnitude of effect. What we're seeing in our clinical data makes us a little bit more optimistic that at 12 months in some of these particularly ambulatory assessment that we'll see a difference that we can tie with the bioassay to make a strong argument that the bioassay is predicted of clinical response. And it should be, as Dr. Rosenfeld was getting into, it's describing the pathogenesis of the disease. It's measuring directly what's going on. It's just a question of how much injury has occurred in a given patient, what's -- and how long it takes for that recovery to take this.

Yes. Maybe, Dr. Rosenfeld, do you want to comment on this as well since we're always getting a lot of questions about it, and you can't comment on the how the FDA will deal, obviously, but, I mean, it does get to the root cause of...

No, I appreciate from the FDA's point of view that this is going to take a back-and-forth conversation because my experience is a small sampling of what's in the room and certainly with the FDA. This is a kind of new territory in my opinion. I have been involved with discussions on other compounds and other disease states. And we're not often in a situation where you have such a direct readout. So I think it's going to take some further discussion with the FDA for them to understand just how relevant this bioassay is. And as we collect more data, I think that discussion will be more informed and successful in my opinion. Because I can just hear in the development of other novel compounds, these -- as they call it, regulatory flexibility is very much present in the right context and with the right data. So I echo what you're saying about the ongoing discussion, but I'm pretty optimistic that they will get it, and it will be a very significant move forward for this program.

Can you probably anticipate that the disease severity here, right, would warrant the flexibility from the FDA?

I do. I mean, the other point, which probably has been mentioned is, to date, at this moment, we don't have a treatment for any of these many forms of Limb-girdle dystrophy, any of these genetic forms. This promises to be the first or among the first treatment of any form of Limb-girdle dystrophy, and that's going to perhaps open the door for a really important unmet need. I definitely echo what Doug said about patients will be happy for whatever to either slow, stop or reverse the progression. These are young people that are -- I'm thinking right now of some of my own patients that they are young people, they want to do simple things that you might take for granted and any improvement would be beneficial. So the combination of the unmet need, the novelty of the approach, a well-tolerated medication, the fact that the bioassay, the disease assay and the clinical assay, all were consistently positive. I think moving forward, the FDA conversations will take on a different tone.

Okay. That's all really helpful. And I guess just a high-level follow-up to that. Do you have any comments on Peter Mark's recent remarks regarding orphan gene therapies? And what components of his statements do you think might apply to this program?

I don't know.

Did you hear that? Did you hear it in the presentation...

I heard in the presentation, that we just heard...

Yesterday.

Yesterday. Actually, I was kind of -- I don't know specifically about that comment relative to genetic therapies. But overall, he echoed this regulatory flexibility that we're here at the FDA to help you, and we want to move these things forward, and we're open personally, I was encouraged a little surprised that he did it in the form. He did, but I was encouraged by the fact that he echoed what a warm and friendly place the FDA could be.

I'll have to echo those observations as well. It was very surprising, to be perfectly frank. And if particularly, he had some very positive comments around accelerated approval pathway, right, which from my perspective are obviously central and critical to what we're doing. The overall tone, if half of what he was suggesting came to pass would be transformative for the rare disease community. Frankly, it would accelerate development. It would have dramatically reduced the burden in developmental costs and regulatory ticket. So I want to be optimistic, but like there was a lot of really good things to...

Our next question comes from the line of Paul Choi with Goldman Sachs.

My first question is for Dr. Rosenfeld and maybe you could provide your thoughts on potentially using ribitol here in a younger population, perhaps kids ages 5 and up who are earlier in their disease course and if you think earlier intervention in this population makes sense. And second, for the company, can you comment on if you've seen any differences either on the bioassay or any other measures between the homozygous and the other populations in terms of the results? And will you be including both populations in your Phase III study?

Yes. So the question about early intervention is a good question, but I'm afraid we don't really know the answer to that because you're really suggesting would be compounds have benefited an asymptomatic person in precluding the subsequent decline stalling off the subset decline. And this is a biochemical therapy, not a genetic therapy. So if the problem, the biochemical problem is not evident in a particular patient, does it make sense to address it so that it doesn't become evident? And I don't think we know that yet. I think as this program develops, perhaps we'll spend a little bit more time looking at early identified patients before they are symptomatic and looking what their assay looks like. It hasn't been the focus now because, obviously, we're -- they're focused on the symptomatic patients. But it's a good question. It's an important question, and we don't have a lot of precedent with other therapies to know if you intervene early in a biochemical treatment, does it preclude the subsequent? But it might not be relevant if there isn't enough impaired like glycosylation in a 5-year old yet, with a medication to repair glycosylation be of benefit. I don't know the answer, but I think it's worth looking at subsequently as the program matures.

And I think in general, the paradigm is that you have subclinical disease before you have clinical disease. And so there's probably some magic point where...

There might be, yes.

We are currently conducting juvenile toxicology studies that will allow us to expand the age range. Our goal is to ultimately have the ability to treat extremely young children. Our expectation is either in clinical study, but especially out, if this was to become commercially available, if there would be -- that question would come up immediately, I would expect. And so it's something that we will be looking to address with data. The second part of the question, it was related to the enrollment criteria and whether we expect to see differences. That's a really important question, and I'm answering it kind of a roundabout way. So the concrete answer to that is -- that we're going to be including both L276I homozygous and non-L276I homozygous patients in our Phase III study. We are going to be stratifying patients based on their genetic profile. So we will have the ability to tease out whether there is a greater or lesser effect in patients who have L276I homozygousity versus other genotypes. You could make a valid argument that the greater impact would be seen in the L276I homozygous based on that really marked increase in ADG glycosylation that we see in the bioassay. Conversely, you could make the argument that, that increase from 5% to 10% that we were seeing in the -- in patients with other genotypes that, that increase, even though it's of a lesser magnitude, maybe of more critical importance by at least getting that -- those levels up to something that's not quite as catastrophic. We are seeing clinical responses in our Phase II study across patients with both genotype populations. Obviously, it's really limited sample size, impossible to teach much from that. But it does suggest that there's a reason to expect that this would have broad applicability.

Our next question comes from the line of Ellie Merle with UBS.

Just in terms of the interim versus final analysis when you can file, I guess is this something we can get visibility on from FDA discussions this year? Or is this something that maybe depends on what you see in the interim data itself and so we won't learn about until after you have the discussions with the FDA with that interim Phase III data in hand? And then just a second question in terms of the dose and any dose response, I guess, for the glycosylated ADG increases, I guess, what was the relationship with the increase in levels and the dose given, I guess, especially those 2 heterozygous patients that have the much greater increase? I guess what dose were those on? And then sorry if I missed it, but I guess did you say what you plan to use for the Phase III dose?

Thanks. I'll kick off, and I'll turn it over to Doug. So I think on the kind of timing of additional clarity on accelerated approval versus non-accelerated approval, we're going to have those discussions with the regulatory agencies kind of middle of this year to the end of this year. And so I think timing of additional clarity will be sometime kind of probably towards the end of this year or first half of next year. And then I'll take it over to Doug for the answer of that question.

So the second question is kind of around dose response and what we're actually using. So the study was because of the realities of rare disease, a little bit limited as far as the numbers to really establish a great story for dose response. We are seeing a continued increase in ADG glycosylation as we move patients in the second part of our study on to a higher dose. We are going to be proceeding into our Phase III study with a dose of 12 grams twice a day with a dose schedule for lower weight patients who receive a slightly lower dose. Looking for that dose selection is based on a number of factors. It's the highest dose in our -- that is within our PK limits with and our -- established for our nonclinical studies. It's the dose that is above the levels at which we see the biggest response in our mouse models, if you're comparing exposure. And it's a dose at which -- which was well tolerated without significant side effects. So given the premise of general, more better up to a point of toxicity, this is the rationale behind our selection and discussed with the FDA, and they agreed with that approach.

Our next question comes from the line of Anupam Rama with JPMorgan Chase.

This is Priyanka on for Anupam. We had a question on the NSAD, which is a key functional endpoint in the Phase III. How variable is this end point because while looking at the drug effect at month 6 versus more, do you anticipate a more linear improvement or an improvement in light of the plateau that you see on like other functional end points?

Thanks. I'll let Doug answer that.

Yes. So the NSAD is a broadly applicable clinical function measure. It was developed and adapted from Duchenne Muscular Dystrophy is to -- adaptive for application Limb-girdle Muscular Dystrophy population. There are a number of limitations to that scale, particular floor and ceiling effect. So very early affected patients may fail to show significant -- any significant impairment on that scale. There's a particular challenge as patients become extremely dysfunctional with minimal function to be able to fully capture the resulting visibility. That said, it's the scale that is broadly applicable, can be used across the broad spectrum of disease. It has been validated and established and accepted, promoted by the regulatory authorities as an unacceptable endpoint to establish clinical impact. Regarding the linear -- question of linearity versus ceiling versus plateauing, this is a scale that in natural history populations in LGMD2i shows a -- from a population basis, consistent and accumulating decline over time. In clinical reality, individual patients may have periods of time relative quiescent and periods of time of relative decline. So obviously, from an individual patient basis, it's tough to predict, but overall population, we're seeing a decline between 1 and 2 points per year on a cumulated basis. The rationale behind the duration of our studies to capture that and demonstrate the deviation and departure from them in treated populations compared to our expectations from the untreated control population.

Our next question comes from the line of Greg Harrison with Bank of America.

This is Mary [ Keonne ] on for Greg. And congrats on the data. I guess with the 12-month interim analysis expected for the Phase III, what would be a clinically meaningful response to this level of follow-up? And then maybe what are your plans for patient visit cadence to evaluate the biomarker and other end points ahead of the interim readout?

Thanks. Do you want to take that question?

Yes. So do you mind repeating the second part of that question? I wasn't quite hearing it ready.

Yes, absolutely. What are your plans for patient visit cadence to evaluate the biomarker and other end points ahead of the interim readout?

Okay. So we'll be following patients in the Phase III study every 3 months for the first 15 months and then 6 months -- every 6 months thereafter. We expect that we'll have a considerable body of data, not just on the core population for the interim analysis, but also other patients who have enrolled but not had a sufficient 12-month period of observation. There'll be a significant body of data that we expect to have at that time. I think the question you asked -- the first part of the question that you asked was regarding the magnitude of effect that we would need to see in clinical measures. Is that the question?

Yes.

Yes. So it's a difficult question for us to answer. In general, stability versus decline is the basis of -- it would be a sufficient for success. I expect -- we expect to see an improvement from baseline at the time of the 12-month analysis that would be the most supportive and robust demonstration of clinical impact. And we'll have to see once the data emerges. If it mirrors the ongoing Phase II study, we have a pretty high expectation of success.

Our next question comes from the line of Dane Leone with Raymond James.

Can you guys hear me?

Yes. Thank you.

Okay. Great. So kind of 2 dumb questions from my end. When you look at the data update from the presentation this weekend versus the last update from last year, some of the point estimates did change and shift a bit on the functional assessments. And I was just curious for the reason that may be. And also, why this time, we don't have a point estimate for month 12 for the actively treated cohort? And then one other just kind of data question. Is there an estimate in terms of the bias that we would expect for the serum CK measurements given the baseline was assessed post functional assessment versus prior to functional assessment and the other time points? And then I have 1 follow-up.

All right. So the -- I'll address this question, if that's all right?

Yes.

The data that was presented in the fall was reflecting the available data at that point. So there was less -- there were a number of subjects who had not completed all the assessments. The -- that 12-month reflection was a -- inadvertent type O was actually reflecting 15 months. So that was a QC mistake in our slides. The question regarding CK is a tricky one to answer. What we observed early in our Phase II study at our initial monitoring visit is that the first 4 subjects that had their CK samples obtained after their functional assessments. Different investigators had different opinions on how much of a magnitude of effect they would have. We did measure the CK amongst those patients in -- from pre-enrollment samples. We cannot include those in our data, but they were markedly elevated at baseline as well. And so the -- while the overall numbers may shift a little bit, the magnitude of effect that we're seeing is still there.

Great. And one kind of longer-term question on the program. Clearly, the clinical feedback has been very positive around the ability to create a biomarker assay that could correlate with improvements and functional assessment over time. Is the view from your team that essentially the kind of the protection of this program from copycat programs would be the proprietary nature of the diagnostic assay more so than the actual functional therapeutic being ribitol in of itself? Or is that not the view?

Yes, I'll take that question. I don't think that's the view. I think that we would anticipate this to have the same type of commercial exclusivity just like any other kind of small molecule therapeutics. So there's probably at least 2 layers of protection here. The first one being IP. We do have IP on the method of use here to treat this disease. And then IP goes out to 2040 with patent-term extensions. And then the second layer of exclusivity here would be, of course, regulatory exclusivity. So at a minimum, we have ODD issued in both U.S. and Europe.

[Operator Instructions] Our next question comes from Suji Jung with Jefferies.

Question on the [ GoodData ]. I just have a quick question on bioassay, regarding the variants and also what is the lower limit detection for detection...

It's kind of hard to hear you, but I think you're asking a question about the variability of the bioassay and lower limited of detection. Is that what you would have asked?

Yes, yes.

Okay.

Yes. So the variance that was described in the assay between 15% and 18%. The issue with regard to the lower limit of detection has been resolved in our current assay. We use a dose -- a protein loading aliquot method that allows us to quantify extremely low levels of expression and something that's particularly important for the non-L276I homozygous patients, many of whom have exceedingly low levels of glycosylated alpha-dystroglycan at baseline.

And maybe I'll speak with other comment about the variation of the assay. We do believe that we're in the same range of others that have used surrogate endpoints for approval like dystrophin. And so we're pretty pleased actually with the performance of the assay.

Yes, exactly.

Great. And for the Phase III design, you mentioned that you're going to include homozygous patients as well. It sounds like those patients declined lower than [indiscernible]. So my question is, can you detect sufficient decline in 12 months? Do you see the separation between the treatment and placebo arm? And finally, what is your commercialization strategy for this program?

So the first question was about...

About the pace of progression in the L276I homozygous patients. Yes, that's the critical issue in the field. The critical conundrum in studying patients with L276I, over short intervals, the demonstrable difference from untreated populations might be relatively modest as an accumulating deficit over time that leads people to call it a slowly progressive disease, but it's one that progresses to an extreme disability. That's the reason why the conventional full study is designed in the way it is. It's to provide a sufficient interval to fully capture those differences. They will emerge over time across both heterozygous and -- or sorry, non-L276I homozygous and L276I homozygous patients. But it may take some time to really realize that in untreated population and given the study underlying basis of the business. I couldn't grasp the second question.

Yes, sorry, just on that point as well, though, I think also, there's a subtlety here in that the study is powered to show a functional improvement at the interim assessment at 12 months. That's not actually what we're looking for them. What we're looking at is the improvement in glycosylated-alpha DG as well as the correlation between the improvement in glycosylated-alpha DG and any improvement in functional improvements at that time. And that subtlety in terms of looking at correlations between those 2 versus just looking an improvement in functional endpoint is a subtle, but important difference in the way, right, we're powering and designing the study. And then -- sorry, we cannot hear your second question.

Sorry, that my last question was about commercialization strategy for this program.

Commercialization strategy for the program. Is that the question?

Was it about commercialization? Sorry, we're a having hard time hearing you.

Yes, it was. I'm sorry about that. Yes.

Yes, did you have a specific question about that? Or was it...

Yes. So are you planning on commercializing it by yourself? Or do you plan to partner it out?

Got it. Yes, I mean, I think that's going to -- that's always a question kind of longer term for BridgeBio. I think we have the best partner mentality. And so I think when we want to able to kind of make a decision about where we think we can -- who can best optimize getting this into patients' hands at that time.

That concludes today's question-and-answer session. I'd like to turn the call back to Neil Kumar for closing remarks.

Well, thanks, everyone, for taking the time. And we appreciate the questions. We're around for further questions as the day evolves. And thanks to the team and to Dr. Rosenfeld for their time as well.

This concludes today's conference call. Thank you for participating. You may now disconnect.