Good day. Thank you for standing by. Welcome to today's discussion with BridgeBio, which will cover the company's novel bioassay, updates on phase 2 data, and the phase 3 trial design for BBP-418 in limb-girdle muscular dystrophy type 2I, known as LGMD2I. At this time, all participants are in a listen-only mode. Please be advised that today's conference is being recorded. I would now like to introduce you to 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 BridgeBio'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, 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 glycosylation levels of the alpha-dystroglycan complex, which I'll refer to going forward as αDG in my comments.
Using both natural history and phase 2 data, we've asked and answered key questions regarding the linearity of αDG glycosylation's 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 αDG 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 αDG glycosylation, argues strongly for the usefulness of this measure in the preliminary assessment of therapeutic efficacy. Third, using this novel bioassay at now updated time points, we demonstrate the approximate doubling of αDG glycosylation levels in both compound heterozygous and homozygous recessive patients. This couples well with improvements across other measures, including CK.
Fourth, perhaps most hearteningly, despite it being open label data, of course, we show improvement at 15 months in key ambulatory and clinical measures for patients on an ongoing phase 2 study. The team will walk through our current phase 3 thinking and design, which seeks the ability to gain approval on αDG glycosylation, given the points made above and coupled with the safe profile of this drug to date and the severity of the unmet need. However, the trial will employ a nested trial design that seeks to establish efficacy in the longer term against a broader set of functional endpoints. 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.
Anna Wade, 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 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 affected 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 need 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. An additional 2,000 patients may be afflicted by related conditions. Glycosylation, as many of you know, of alpha-dystroglycan is regulated by three enzymes that each use sugar ribitol as a common substrate. The other two outside of FKRP, which is mutated in LGMD2I being ISPD and FKTN. Our approach could, in theory, work for all three 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. 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 3 later this year, it will join another three programs in Phase 3, including our efforts in ATTR cardiomyopathy, achondroplasia, and ADH1, all conditions with large unmet need. 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 of the Department of Neurology and the director of the Center for Restorative Neurology at Loma Linda University Health. His clinical activities over the past quarter-century plus have 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. 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? 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. Over 10 years from 2000 or a little bit before that till 2010, there's what's almost an explosion of subtypes of limb-girdle dystrophy. These were largely defined by individual protein mutations.
Whereas we used to call this, you know, collectively a wastebasket 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. That wasn't sufficient anymore. For the past, perhaps, 10 to 15 years, it's not been sufficient. You have to say what type. That type is defined by particular mutations. We actually. That explosion was so significant that we wrote letters to designate the different forms of dystrophy. 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 gonna 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, a treatment. We've gone one more step past the individual descriptions by the mutations now are actually gonna ameliorate and hopefully treat patients with this condition. Next slide, please. Thank you. 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 haven't screened as many patients. Now that there could be potentially a treatment, there might be in my clinics anyway, patients that are now worth a second look to see. The disability of a patient with limb-girdle 2I is not subtle.
It's a little delayed, you'll see in a subsequent slide, but loss of ambulation in early life, late childhood, early teens. Respiratory decline is not uncommon, and cardiac dysfunction is quite common. By adulthood, this is a fairly pervasive disability. We're now on slide 10. As you can see, by comparison to other types of FKRP mutations, there is a bit of a distinction here. The onset of the homozygous L276I 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 running in late childhood or perhaps some falls. 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.
As you heard before, cardiac dysfunction is fairly common. 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. Now I'll turn this back over to Dr. Sproule.
All right. Thank you. 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, I wanted to kind of reiterate a couple critical points. As Dr. Rosenfeld noted, LGMD2I is a genetically defined disease caused by biallelic mutation of the FKRP gene. FKRP is an enzyme that's critically needed for glycosylation 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.
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. I'll show how glycosylated alpha-dystroglycan levels are consistent with that established patterns of clinical severity seen in patients with different genotypes. The L276I homozygous genotype versus patients with other typically more severe genotypes. I will also talk through, as Neil mentioned, our early clinical data that we're seeing from our phase 2 study.
And in contrast to the expected decline in clinical function that's seen over intervals of a year or more in untreated populations, I'm gonna show our early phase 2 results, which suggest improvement in not just glycosylated alpha-dystroglycan, but also other laboratory markers such as creatine kinase and clinical measures, after 15 months of treatment with BBP-418. We can go to slide 13. This schema outlines both the pathophysiology as well as the therapeutic mechanism that post-therapeutic mechanism of action of BBP-418. A BBP-418 is a synthesized version of endogenous ribitol provided in a powdered form dissolved in water and taken orally. On the left side of the figure, we see what happens in the untreated disease state.
We have partial loss of function mutations in FKRP, and this results in widespread dysfunctional, hypoglycosylated alpha-dystroglycan and myocytes. 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. While the FKRP enzyme is deficient and dysfunctional, there's still some residual enzyme activity. It's obligatory for life. Providing super physiologic levels of the substrate for that enzyme, you can harness that residual FKRP enzyme activity, drive increased full-length functional glycosylated alpha-dystroglycan. You can go to slide 14.
As Neil mentioned, ML Bio has developed a novel validated bioassay to measure glycosylated alpha-dystroglycan that can quantify differences associated with FKRP status as well as the BBP-418 treatment. This western blot-based assay uses muscle tissue obtained from the tibialis anterior muscle and has been validated for use in the clinic as a sensitive, specific, and robust measure of glycosylated alpha-dystroglycan. 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. This slide shows an example of the bioassay output as applied to patients in the phase 2 study. It shows how we can measure a potential response to therapy in LGMD2I.
On the left column is a western blot, run from a pretreatment baseline sample. What you can see or not see is, you know, there's very little glycosylated alpha-dystroglycan, which is reflected in those yellow bands across the top. Most of the species that you're actually measuring are that are seen in green, particularly lower, are non- or hypoglycosylated alpha-dystroglycan species. In contrast, with, you know, following BBP-418 treatment, we see an increase in that yellow band. That's the fully glycosylated alpha-dystroglycan. That middle column is after three months. The right column is after six months of treatment. You can appreciate the increasingly bright signal which reflects increased glycosylated alpha-dystroglycan in the muscle tissue sample.
If you move to slide 6.
Can I make a comment?
Oh, yes, please.
Can you go back that slide? You know, I just wanna make a comment because for me, this is personally the most exciting part about this program. To call this a bioassay is perhaps only 'cause we don't have a better word. Most bioassays reflect something that's going on in the disease state. That would be the case of CPT for a lot of muscle diseases. This is more than that. This is a assay that is actually measuring the disease. The disease is impaired glycosylation, and this assay is measuring glycosylation. it, if you will, it doesn't get better than that with regard to disease activity. I wish I had this kind of direct readout of disease activity with many of the other diseases that I treat.
That really got my attention when I was first being oriented to the program. I just wanna emphasize that we call it a bioassay. Perhaps it's a disease assay, is 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.
Oh, no. Thanks very much.
Just share my perspective on what's different.
Absolutely. You know, moving to slide 16. This is a schematic, kind of outlays or outlines our ongoing and completed clinical program. We've completed one natural history study. We have a phase 2 study that's ongoing, and we're about to start our phase 3 study. The MLB-01-001 is a 12-month non-interventional natural history study that is intended to provide longitudinal assessments that would be done in a conventional clinical trial to provide a really robust data comparison with our ongoing studies. It's 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 into for enrollment as we move into our phase 3 study. ML-003 study is our phase 2 study. It's an open label ascending dose study of BBP-418 in patients with LGMD2I. I'll talk more about ML-005, which is our phase 3, which will be a large multi-center, 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 is that there's two distinctly different populations from a clinical severity standpoint. Patients who are homozygous for the L276I mutation, the so-called common or Viking mutation, tend to present somewhat later and have a less rapidly progressive disease course when compared with patients with other genotypes. Typically, 1 L276I mutation and 1 more severe, not uncommon, but pathogenic mutation. As we would expect based on those established differences in population, between the less severe L276I homozygous and the typically more severe phenotype seen amongst patients with other genotypes, we see this when we look at the bioassay as well.
The L276I homozygous patients show a less severe reduction in glycosylated alpha-dystroglycan, approximately 11% of what we would expect from normal tissues, normal controlled tissues, versus approximately 5% in patients with other genotypes when compared with healthy controlled tissues. It's profoundly reduced across all patients, compared with what one would expect to see in healthy patients. This, moving to slide 18, this is a schema that's for our ongoing phase 2 study. This ML-003 study is an ongoing open-label, single-site dose escalation phase 2 study involving 14 patients. In addition to safety, efficacy measures including the NSAD, 100-meter time test, 10-meter walk test, FVC, FEV2.0. We're also assessed longitudinally.
Obviously, we measured longitudinally the glycosylated alpha-dystroglycan levels, based on the anterior biopsy, as we described, and creatine kinase and other measures. This is a broad study. It enrolled ambulatory, non-ambulatory patients. It enrolled patients with L276I homozygous and non-L276I homozygous genotypes. It's a small study, but it's a very broad heterogeneous population to provide a pretty reasonable encapsulation of the patient population. If you can go to the next slide. This is a safety profile. This is to this date, 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 appropriate with any program.
We're extremely reassured by the 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 of grade 1 or grade 2 in severity, self-limited, not ongoing. No discontinuations or interruptions in therapy have been required. There have been three severe adverse events that have been all completely unrelated to this therapy and reflect the severity of the underlying condition. If you can go to slide 20. This is I think where we get most excited, or I personally get most excited about the results that we're seeing. Again, this is a small study.
It's only 14 patients. What we're seeing is the impact of treatment with BBP-418 on alpha-dystroglycan glycosylation on the left. The box plots in forest green are the L276I homozygous patients. What you're seeing there is an increase from a baseline median of approximately 17% to a median of over 40% by month 15. It's more than doubling that we're seeing glycosylated alpha-dystroglycan levels in the L276I homozygous patients. In patients with other genotypes, they're much more severely affected. They're starting with a median of around 6%. We're seeing an increase to a median of around 10%, which is, you know, not quite, but close to approximately doubling in that population as well.
That's obviously a very marked increase, relative to the baseline. Certainly we could talk more about it, but it's certainly an extremely intriguing result. 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, I don't know if you have any comments on this.
No, I think this actually reflects the point I was making earlier that, you know, 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. Of course, they're gonna correlate because one is reflecting the other. Like the alpha-DG assay is so much more to the point of it. I share your enthusiasm for this slide 'cause it really highlights the novelty and the impact of this program.
If you can go to 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. You know, 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 to work to translate, to impact on the organ and ultimately to clinical function. 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 time test, which is in the middle box.
On the right, we are seeing an increase in the NS score, all increases from baseline in the Phase 2 patients, and that is what is shown in the red dashed line. 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 is the expectation of what would happen over the population as a rough comparison between these two groups. If you go to slide 22. You know, we are very excited. To me, the data we see from the Phase 2 just really creates a groundswell of enthusiasm, at least internally, and hopefully external as well, to move this program forward in the next phase of development.
We're very excited to announce, as we did yesterday, our plans for our Phase 3 trial, which are expected to start this summer. This will be a two-to-one randomized placebo-controlled double-blind study of BBP-418 in 80-100 patients with LGMD2I. The full study will involve 36 months of treatment with NSAD as the primary endpoint. We do plan to conduct an interim analysis at the time that approximately 40 patients have completed at least 12 months of follow-up, and that's going to be focused upon change in glycosylated alpha-dystroglycan. Hopefully the data will be just as robust as we've already seen in our Phase 2 study, supported by selected clinical endpoints and other laboratory markers.
We're discussing strategy for accelerated approval with the regulatory agencies. We'll disclose more in the future as those conversations mature and move along. 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 today.
I'll moderate this here. Yeah.
All right. Well, thanks everyone for your comments. We'll move into Q&A at this point, and I'll turn it over to Christine Siu to moderate that section.
As a reminder, to ask a question, please press star one one on your telephone. Please stand by while we compile the Q&A roster. Our first question comes from the line of Salim Syed with Mizuho.
Hi, this is Venice for Salim. Thanks for the call and for taking our questions. 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? 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? Thank you.
Yeah. Maybe I'll turn over to Doug to answer the initial question and then comment.
Yeah.
Yeah.
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. 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 its easy accessibility and re-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. In the natural history study, there were three biopsies scheduled and performed on patients.
patients, it was 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.
Yeah. Then maybe I'll just take the last part of your question, which is about using the assay as a basis for, you know, a surrogate endpoint. You know, that's clearly part of our strategy here, given the high conviction we have in this therapeutic hypothesis. You've heard, you know, the excitement around the use of this assay and the fact that it is really directly measuring the cause of the disease. You know, we're obviously designed this therapeutic to around that whole hypothesis. We do have a series of interactions planned with the FDA and other regulatory agencies to discuss the potential to use that surrogate endpoint. We'll have, you know, more to say obviously later as we have those discussions.
It is something we have high conviction around and, part of our strategy.
Got it. Thank you very much.
Our next question comes from the line of Mani Foroohar with SVB Securities.
Thanks for taking the question and for the update. You talked about your engagement with regulatory authorities. Where are we in terms of nailing down regulatory feedback, getting FDA minutes, et cetera, around what would be an approvable profile at the interim analysis? You know, have you explicitly gotten feedback around what you need to show on the assay data, what you need to show on clinical endpoint? Is that still an ongoing discussion? How does that inform your conduct of the study of the design of the phase 3 , obviously?
Yeah. Thanks, Mani. I'll kick off the answer to this question, and I'll turn over to Doug if there's any other comments. We've already had a lot of discussions with the FDA on designing a pivotal study. Not just the FDA, but other regulatory agencies as well. 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 discussions subject to whether the accelerated approval pathway could be open to us. We don't have a lot more detail 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.
All right. Thanks. That's helpful.
Our next question comes from the line of Tyler Van Buren with Cowen.
Hi, this is Tara on for Tyler. We're wondering if it's possible to file on an accelerated basis in the phase 3, based on improvements in the biomarkers like the ADG or C.K. earlier than 36 months, perhaps even six months based on what you saw in with your bioassay at that time, or if you think you'll have to wait, 12-18 months for functional endpoint confirmation? Thanks.
Yeah. I can kick this off and also turn over to Doug later. I mean, I think that's certainly a good question. I think we have looked at the data and also wondered that ourselves. It's, you know, if you look at the data, clearly you can see, you know, massive improvement in the biomarkers at three months. The way we've designed this interim analysis, however, is to take advantage of that magnitude, right, of change at three months, also to look at trying to correlate it to functional improvement at 12 months, right? Trying to get at are the biomarkers reasonably likely to predict a clinical benefit? That's kind of some of the principles behind how we've designed the interim assessment.
You know, again, right, we have high conviction in that strategy, but that is also subject to our discussions with the FDA and other regulatory agencies. I don't know, Doug, if you...
Yeah, I think, you know, 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, just keep me from getting worse, that would be a huge win. We believe that this product could do more. At the same time, if that's all it did, that's a major advance for the community. Our pivotal the full study is built around 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 assessments, that we'll see a difference that we can tie with the bioassay to make a strong argument that the bioassay is predictive of clinical response. 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 place.
Yeah. Maybe Dr. Rosenfeld, you wanna comment on this as well, since we're obviously getting a lot of questions about it. I mean, you can't comment on how the FDA will view it, obviously.
Right.
I mean, it does get to the root cause of
I can appreciate from the FDA's point of view that this is gonna take a back and forth conversation because, although my experience is a small sampling of what's in the room and certainly with the FDA, this is a kinda new territory, in my opinion. I have been involved with discussions on other compounds and other disease states, and we're not often in this situation where you have such a direct readout. I think it's gonna take some further discussion with the FDA for them to understand just how relevant this bioassay is. As we collect more data, I think that discussion will be more informed and successful, in my opinion.
I can just, you know, hear in the development of other novel compounds the, as they call it, regulatory flexibility is very much present in the right context and with the right data. 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.
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 treatments of any form of limb-girdle dystrophy. That's gonna 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. You know, these are young people. I'm thinking right now of some of my own patients, that they're young people. They wanna do simple things that you might take for granted, and any improvement would be beneficial.
The combination of the unmet need, the novelty of the approach, the 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, thanks. That's all really helpful. I guess just a high-level follow-up to that, do you have any comments on Peter Marks' recent remarks regarding orphan gene therapies? What components of his statements do you think might apply to this program?
I don't know.
Did you hear that? Did you hear his presentation?
I heard. Oh, you mean the presentation that we just heard?
Yesterday.
Yesterday? Actually it 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 wanna move these things forward, and we're open. Personally, I was encouraged. A little surprised that he did it in the forum that he did, but I was encouraged by the fact that he echoed what a warm and friendly place the FDA could be.
I have to, yeah, I'll have to echo those observations as well. It was very surprising, to be perfectly frank. If... You know, particularly he had some very positive comments around accelerated approval pathways-
Right.
which from my perspective are obviously central and critical to what we're doing. His overall tone, if half of what he was suggesting came to pass, would be transformative for the rare disease community, frankly, 'cause it would, it would accelerate development. It would dramatically reduce the burden, in developmental costs and regulatory stickage. I wanna be optimistic. Yeah, like, there was a lot of really good things that came out of that, so.
Maybe next question.
Our next question comes from the line of Paul Choi with Goldman Sachs.
Hi. Good morning, and thanks for taking our questions. My first question is for Dr. Rosenfeld, and, you know, maybe you could provide your thoughts on potentially using ribitol here in a younger population, perhaps, you know, kids ages five and up who are earlier in their disease course, and if you think earlier intervention in this population makes sense. 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? Will you be including both populations in your phase 3 study?
The question about early intervention is a good question, but I'm afraid we don't really know the answer to that 'cause you're really suggesting would the compounds have benefit in an asymptomatic person in precluding the subsequent decline, stalling off the subsequent decline. This is a biochemical therapy, not a genetic therapy. 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? 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're 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. 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? It might not be relevant. If there isn't enough impaired glycosylation in a five-year-old yet, would 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.
Yeah. I think in general, the paradigm is that you have sub, subclinical disease before you have clinical disease. There's probably some magic point where-
There might be. Yeah.
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, you know, if this was to become commercially available, there would be. That question would come up immediately, I would expect. It's something that we will be looking to address with data. The second part of the question was-
The homozygous version.
was related to the enrollment criterion, whether we expect to see differences. That's a really important question. I'm gonna answer in a kind of roundabout way. The, the concrete answer to that is that we're going to be including both L276I homozygous and non L276I homozygous patients in our phase 3 study. We are gonna be stratifying patients based on their genetic profile, so we will have the ability to tease out whether there's a greater or lesser effect in patients who have L276I homozygosity versus other genotypes. You know that you could make a valid argument that the greater impact would be seen in the L276I homozygotes based on that really marked increase in αDG glycosylation that we see in the bioassay.
Conversely, you could make the argument that increase from 5% to 10%, that we were seeing in patients with other genotypes, that increase, even though it's of a lesser magnitude, may be 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 2 study across patients with both genotype populations. Obviously, it's really limited sample size, and impossible to tease much from that. But it does suggest that there's reason to expect that this would have broad applicability.
Okay, great. That's, thanks for the context and taking our questions.
Our next question comes from the line of Ellie Merle with UBS.
Hey, guys. Thanks so much for taking the question. Just in terms of the interim versus final analysis and when you can file, I guess, is this something we can get visibility on from FDA discussions this year? 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 3 data in hand. Just a second question in terms of the dose and any dose response. I guess for the glycosylated, αDG increases, I guess what was the relationship with the increase in levels and the dose given, I guess, especially those, two heterozygous patients, that had the, you know, much greater increase? I guess, what dose were those on?
Sorry if I missed it, but I guess, did you say what you plan to use for the phase 3 dose? Thanks.
Thanks. I'll kick off, and I'll turn it over to Doug. I think on the kind of timing of additional clarity on accelerated approval versus not accelerated approval, we're gonna have those discussions with regulatory agencies kind of middle of this year to the end of this year. I think timing of additional clarity will be, you know, sometime kind of probably towards the end of this year or first half of next year. I'll kick it over to Doug for the-
Yeah.
dose question?
The second question is kind of around dose response and what we're actually using. 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 αDG glycosylation as we move patients in the second part of our study onto a higher dose. We are going to be proceeding into our Phase 3 study with a dose of 12 grams twice a day with a dose schedule for lower weight patients who receive a slightly lower dose. Reason for that dose selection is based on a number of factors. It's the high...
It's the highest dose in our that is within our PK limits with and are established for our non-clinical 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. At it's a dose which was well tolerated without significant side effects. You know, given the premise of, in general, more is better up to a point of toxicity, this is the rationale behind our selection of the dose. Discussed with the FDA, and they agreed with that approach.
Great. Thanks.
Our next question comes from the line of Anupam Rama with JPMorgan Chase.
Hi, this is Priyanka on for Anupam. We had a question on the NSAD, which is a key functional endpoint in the phase 3. How variable is this endpoint? Because while looking at the drug effect at month 6 versus more, do you anticipate a more linear improvement or an improvement like the plateau that you see on, like, other functional endpoints?
Thanks. I'll let Doug answer that.
The NSAD is a broadly applicable clinical function measure. It was developed and adapted from Duchenne muscular dystrophy. It was adapted for application in limb-girdle muscular dystrophy population. There are a number of limitations to that scale, particularly floor and ceiling effects. Very early-affected patients may fail to show significant any significant impairment on that scale. And there's the particular challenge if patients become extremely dysfunctional, with minimal function being able to fully capture the resulting disability. That said, it's a scale that is broadly applicable, can be used across the broad spectrum of disease. It has been validated and established and accepted and promoted by the regulatory authorities as an acceptable endpoint to establish clinical impact.
Regarding the question on 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 of relative quiescence and periods of time of relative decline. Obviously from an individual patient basis, it's tough to predict. Over a population, we're seeing a decline between 1 and 2 points per year on an accumulated basis. The rationale behind the duration of our study is to capture that and demonstrate the deviation and departure from that in treated populations compared to our expectations from the untreated control population.
Thank you.
Our next question comes from the line of Greg Harrison with Bank of America.
Good morning. This is Mary Keown for Greg. Thanks for taking our question and congrats on the data. I guess with the 12-month interim analysis expected for the phase 3, what would be a clinically meaningful response to this level of follow-up? Then maybe what are your plans for patient visit cadence to evaluate the biomarker and other endpoints ahead of the interim readout? Thanks.
Yeah, thanks. Do you wanna take that question?
Yeah. Do you mind repeating the second part of that question? I wasn't quite hearing it right.
Absolutely. What are your plans for patient visit cadence to evaluate the biomarker and other endpoints ahead of the interim readout?
Okay. We'll be following patients in the phase 3 study, every three months for the first 15 months and then every six 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 will have enrolled but not had, you know, sufficient 12-month period of observations. 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.
It's a difficult question for us to answer. In general, stability versus decline is the basis of it would be as sufficient for success. I expect we'll need 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. We'll have to see once the data emerges. If it mirrors the ongoing phase 2 study, we have a pretty high expectation of success.
Great. Thank you.
Our next question comes from the line of Dane Leone with Raymond James.
Hello. Can you guys hear me?
Yes. Thank you.
Okay, great. Thanks for taking the questions. Kind of two 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. 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. Then one other just kinda data question. Is there, 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 in the other time points? I have one follow-up.
Thank you.
All right. I'll address those questions if that's all right.
Yeah.
The data that was presented in the fall was reflecting the available data at that point. There was less, there were a number of subjects who had not completed all the assessments. The that 12-month reflection was an inadvertent typo. It was actually reflecting 15 months, 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 2 study, at our initial monitoring visit is that the first four subjects had their CK samples obtained after their functional assessment.
Different investigators have had different opinions on how much of a magnitude of effect that would have. We did measure the CK amongst those patients in pre from pre enrollment samples. We cannot include those in our data, but they were markedly elevated at baseline as well. While the overall numbers may shift a little bit, the magnitude effect that we're seeing is still there.
Great. One kind of longer-term question on the program. Clearly, you know, 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, you know, 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? Thank you.
Yeah, 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 exclusivities just like any other kind of small molecule therapeutic. There's probably at least two layers of protection here. The first one being IP. We do have IP on the method of use here to treat this disease, IP goes out to 2040 with patent term extensions. The second layer of exclusivity here would be, of course, regulatory exclusivity. At a minimum, we have ODD issued in both U.S. and Europe.
Thank you.
As a reminder, to ask a question, that's star one one. Our next question comes from Suji Jeong with Jefferies.
Hi, I'm calling on the good data, and thanks for taking my question. I just have a quick question on the bioassay regarding the variance and also, what is the lower limit for the?
It's kinda hard to hear you, but I think you're asking a question about the variability of the bioassay and lower limit of detection. Is that what you asked?
Yeah. Yeah. Yes.
Okay.
Yeah. Let me try to pull my, pull up the slide. We had the, there, the variance that was described in the assay between 15% and 18%. The issue with regards 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. This is something that's particularly important for the non L276I homozygous patients, many of whom have exceedingly low levels of glycosylated alpha-dystroglycan at baseline.
Maybe I'll just make one 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 ELEVIDYS, and so we're pretty pleased actually with the performance of the assay.
Yeah, exactly. Thank you.
Great. Thank you. For the phase 3 design, you mentioned that you're gonna include homozygous patients as well. It sounds like those patients declined lower than . My question is, can you detect sufficient decline at 12 months due to the separation between the treatment and placebo arm? Finally, what is your commercialization strategy for this program? Thank you.
The first question was about.
About the pace of progression in the L 2-
Yeah.
In the L276I homozygous patients. Yeah, that's the critical issue in the field. It's the critical conundrum in studying patients with LGMD2I. Over short intervals, the demonstrable difference from untreated populations might be relatively modest. It's an accumulating deficit over time that leads people to, you know, call it a slowly progressive disease, but it's one that progresses to a extreme disability. That's the reason why our, 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.
It may take some time to really realize that, in given this, the underlying basis of this disease.
Yeah.
I couldn't grasp.
No, sorry. Just on that point as well, though. I think also there's a subtlety here in that the study isn't powered to show a functional improvement at the interim assessment at 12 months. That's not actually what we're looking for then. 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. That subtlety in terms of looking at correlation between those two versus just looking at improvement in functional endpoint is a subtle but important difference in the way, right, we're powering and designing this study. Sorry, we cannot hear your second question.
Oh, sorry. My last question was about commercialization strategy for this program.
What?
Commercialization strategy for the program. Is that the question, ma'am?
It was about commercialization? Sorry, we're having a hard time hearing you.
Yeah, I was. I'm sorry about that. Yeah.
Yeah. Did you have a specific question about that, or was it?
Yeah. Are you planning on commercializing it by yourself or do you plan to partner it out?
Oh, got it. Yeah. I mean, I think that's gonna, that's always a question kind of longer term for BridgeBio. I think, you know, we have the best partner mentality, and so I think, you know, we'll when we get to it, we'll kinda make a decision about where we think we can, who can best optimize getting this into patients' hands at that time.
Great. Thank you.
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.