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

Good day, and thank you for standing by. Welcome to the BridgeBio Pharma to discuss Phase II data for BBP-418 in limb-girdle muscular dystrophy Type 2i conference call. [Operator Instructions] Please be advised that today's conference is being recorded. [Operator Instructions] And now I would like to hand the conference over to Mr. Neil Kumar, CEO of BridgeBio Pharma. Thank you. Please go ahead, sir.

Well, thank you so much, operator, and thanks, everyone, for joining us as we discuss some exciting new data from our program targeting the disease, the large and devastating to the limb-girdle muscular dystrophy Type 2i. Before we begin, I just want to make a quick reminder. We'll be making some forward-looking statements today, which are based on our current expectations and beliefs. As such, these statements are subject to certain risks and uncertainties, and I'd encourage everyone, as you know, to consult the section entitled Risk Factors in our most recent annual report on Form 10-K filed with the U.S. SEC and in subsequent filings made by us with the SEC, which are available on the SEC's website. Okay. I want to take a quick moment and introduce the leader of our efforts in LGMD2i, Dr. George McLendon. His CV is very long and storied, he has been a chemistry professor PhD, Chairman of the Department of Chemistry at Princeton and Dean of Arts and Scienes with the Duke University. He also cofounded 6 various startups in genetic diseases and elsewhere 4 of which have had exits and he's been leading our efforts here to target this well-described disease at its source over the past couple of years with a small but very, very able team. So let me pass it over to George to introduce the program and then he will, in turn, introduce some of our other speakers to walk through the data that we'll be presenting today, MDA. George?

Thank you, Neil, and thanks all of you for being on the phone. As Neil likes to say, BridgeBio was founded to put patients first and the ML Bio subsidiary is what's founded actually by patient families to serve patients and their families through the McCall-Lockwood lab, which is at Atrium Health. Dr. Qi Lu at McCall-Lockwood lab developed an idea that the FKRP mutation, which lies at the heart of LGMD2i might be rescued if you could supplement the substrated high enough concentrations to force the substrate to bind and therefore, force the enzyme back to work. And that idea turned out in a syngeneic mouse model to work. So the next question then was, how do we stop curing mice and start curing people? And for that, we needed a partner, and we looked at a number of different options as we were spinning that technology out of Atrium where I was serving as the Vice President of Research at that time and found BridgeBio. And what was so exciting to us about BridgeBio was that they had built-in expertise that could enable us to move much more quickly, and I'm excited today to be able to say that less than 3 years after we started, we're now able to report what I believe is very exciting Phase II data and we'll be in Phase III shortly thereafter. So that's the -- that's sort of the time line. And for those of you who know drug development, moving that fast from a nature paper to Phase III is really something. So let's just move to what is LGMD2i? Next slide, please. So Type 2i is an autosomal recessive disorder that leads to partial loss of function in the FKRP gene. What this gene does is in order to stabilize your muscles, they're basically connected to one another and held together by a sugar polymer. And if the enzyme FKRP can't make that polymer, then your muscles become -- your muscle's cells become much weak, much less stable. So BBP-418, the drug that we're using is, in fact, a substrate for FKRP. And as Dr. Lu had hypothesized at the therapeutic doses, you can force the enzyme to bind that sugar and restore function. There's about 7,000 patients in the European Union and the United States who might benefit from such therapy. And as you'll see with this agent, which is first-in-class as disease-modifying agent, should be first treatment to be approved, we hope, and has an excellent safety and efficacy alongside really simple oral dosing. So everything about this agent -- I've been involved in developing other drugs, this is a truly remarkable one. And to tell you more about that, we're going to go to Dr. Peter Kang who is an expert on limb-girdle muscular dystrophy who will tell us more. Peter?

Thank you. Good morning, everybody. So if you go to Slide 6, limb-girdle muscular dystrophy type 2i is a progressive neuromuscular disease. It has a high unmet need, and there are estimated to be 7,000 patients in the U.S. and the European Union. There is a common genetic mutation that is found frequently. The onset tends to be typically early in childhood. This is a fairly serious disease with multiple complications, including loss of ambulation, respiratory complications and cardiac dysfunction. There are no approved disease-modifying treatments for this. The current standard of care is symptom management, which really doesn't alter the progressive decline for these patients. So on the next slide, Slide 7. BBP-418 or ribitol is being investigated as an upstream substrate to drive this residual activity of the mutant enzyme. So the alpha-dystroglycan protein is glycosylated, meaning that there are sugars that are attached to it. And one of the sugars is ribitol, and normally, the ribitol helps to produce what's a cushioning effect as alpha-dystroglycan binds to other proteins like laminin. When you have mutations in this FKRP enzyme, then the ribitol is not really attached properly. So the aim of the therapy is to provide more of the ribitol, and it's orally administered. And that way, you can actually help the alpha-dystroglycan bind to other proteins and produce on more normal function. So if you go to the next slide, Slide 8. We have a full Part 1 and partial Part 2 data available from Phase II. In Part 1, there is a dose escalation. There are 14 participants over a period of 90 days, and there are 3 different dose levels, as you can see. There are 6 grams daily, 6 grams twice a day and 12 grams twice a day. And then in Part 2, everybody was escalated to the maximum dose. There are 3 key study objectives, safety and tolerability, dose selection for the subsequent Phase III and then key biomarker parameters. And then there were 6 key endpoints, creatine kinase, the ratio of glycosylated alpha-dystroglycan, the total alpha-dystroglycan, the north star assessment for dysferlinopathy, the PUL 2.0, a 10-meter walk test and forced vital capacity. And I will now hand it over to Dr. Sproule.

Yes, good morning, and thank you for that sound overview, Dr. Kang. If you go to Slide 10, this is to summarize is what I'm going to talk about over the next couple of slides thereafter. I want to kind of level set as far as what we would expect. And I'll talk more about the -- our ADG rate glycosylation assay in just a second as well as the role of creatine kinase. But just to kind of level set what we would expect. Alpha-dystroglycan should be fully glycosylated in a healthy state. And so what we would expect is that if you took a ratio of the proportion of glycosylated ADG, the total AG that, that range should be -- that, that ratio should be in the vicinity of 1. We see in LGMD2i patients is that with some variability they generally have a ratio in the vicinity of 0.6. So obviously deficient, and that's what leads to the underlying disease. What we would expect based on animal data is that at least a 10% increase in that ratio would be necessary to drive a phenotypic change. And I'll talk more about the results in a second. But what we see early on from our Phase II study is an over 40% increase from baseline on average in the ADG ratio. Creatine kinase is a marker of muscle injury breakdown and release of intracellular protein. There's a great deal of variability that can be seen in the specific levels in healthy individuals based on a number of factors, muscle mass, age, intercurrent illness, et cetera. But generally, a level of below 200 international units per liter is what would be expected to be seen in a healthy state. LGMD2i patients, because of that chronic muscle breakdown, wind up having massive increases in their levels, often well over 1,000, sometimes over 10,000 international units per liter, a dramatic increase from what you would see in patients or in healthy individuals. While there's no defined marker, approximately 50% decrease from baseline would be considered a pretty marked response, and we're seeing well over a 70% decrease from baseline, and I'll talk about this more in a second as well. Lastly, when we talk about clinical function measures, LGMD2i is marked by chronic, slowly progressive but progressive disease over time leading to accumulating disability. And what we would like to see in a therapeutic -- effective therapy is at least a slowing of that decline. And what I'll talk about with our 10-meter walk test results thus far, their early results, but they actually suggest an improvement in clinical function from baseline. So if you can go to Slide 11, we see that, as expected, BBP-418 has shown a strong and reassuring safety profile in patients. Of the 58 adverse events that are seen thus far in our Phase II study, only 8, all low grade, are deemed to be possibly or probably related to therapy. These are self-limited gastrointestinal manifestations, which is not -- and the safety profile is not surprising given that BBP-418 is an endogenous substance that's naturally produced by the body. If you can move to Slide 12. We have developed an assay that measures fully functional, fully glycosylated ADG as a proportion of the total amount of ADG within muscle tissue. And we call this the ADG glycan to total ADG ratio. We've previously showed samples from untreated patients with LGMD2i have reduced fully glycosylated ADG when compared with healthy control tissues. An effective disease-modifying therapy for LGMD2i addresses the root cause of the disease, which is defective and deficient glycosylation of ADG, would be expected to increase that ratio of fully glycosylated ADG ideally towards the levels that are seen in healthy tissues. And here, we show that an average increase of more than 40% across all 3 cohorts in the ADG glycan to total ADG ratio was seen, which is data that is consistent with a possible therapeutic response, at least on a cellular level. If you go to Slide 13, creatine kinase or CK is a marker of muscle injury and breakdown that's widely used in the neuromuscular disease community. In the context of an ongoing muscular dystrophy such as LGMD2i, the failure to effectively stabilize the muscle cell membrane leads to chronic injury and breakdown with release of muscle specific proteins such as CK. An effective disease modifying therapy would be expected to restore that protein apparatus stabilizing function, which would stabilize muscle cells leading to a reduction in CK levels. And in our Phase II study after 90 days of treatment and in many patients over 180 days of treatment, we see a sustained and continued reduction in CK levels. In our Phase II study, we've see an average of more than a 70% decline from baseline. And again, in every single patient has experienced at least some degree of decline. Moving to Slide 14. As one would expect in a disease-modifying therapy, we do see a nice correlation between increases in ADG glycosylation and decreases reduction in creatine kinase levels. If you move to Slide 15, while it's early to expect to see any impact of a therapy on clinical markers, we're really intrigued by the early response that we're seeing in measures such as the 10-meter walk test. What we've seen here is a modest but consistent increase in velocity and walking speed on this test following therapy across all 3 dosing cohorts. And you can see that in the 3 solid spaghetti plot lines in the figure on the left. And this contrasts nicely with the decline in walking speed that we've seen over the 6 months of [ prior to line ] therapy in those same patients, and you see that trajectory projected in the dotted lines on the figure, showing a separation between response before or progression before and progression after initiation of therapy. We're excited to see how patients continue to respond as they have more time on treatment. And certainly, we'll be very interested to see how patients are 6, 9, 12 months after initiation of therapy. So moving to Slide 16 just to summarize what I just talked about. We presented the Phase II Part 1 and partial Part 2 data. This has showed a 43% increase in the ratio of glycosylated alpha-dystroglycan the total [ operates ] to glycan and approximately 70% reduction increase in kinase from baseline at day 90 and 77% reduction at day 180 following therapy. We've seen improvements in functional benefits observed at 90 days when compared with the natural history of the disease. We have seen that BBP-418 has been well tolerated to date across a wide range of dose levels with no observed treatment-related serious adverse events, dose-limiting toxicity or need to discontinue therapy. I haven't talked about this, but there's a portfolio of issued and filed patents that are expected to provide market protection for the foreseeable future. And we've been granted Fast Track designation by the FDA and orphan drug designation, both by the FDA and the European Medicines Agency, which further supports our work. And we are very excited to have our upcoming interactions with the FDA to continue to present the complete Phase II data as it emerges, to initiate our Phase III registrational study, as soon as we can get it rocking. So with that, I'll pass -- I'd like to hand the mic back over to Neil Kumar, CEO of BridgeBio for concluding remarks and question-and-answer.

Thanks so much, Doug, and thank you to the entirety of the speakers. Operator, we're happy to take Q&A now.

[Operator Instructions] Our first question comes from the line of Mani Foroohar from SVB Securities.

Can you give us a sense of where you are in your previous discussions with regulatory authorities? And more broadly, how we should think about potential endpoints for a pivotal? I know this is an indication where there hasn't been a lot of late-stage development. So if you could sort of sketch out how you think about the possible structures of the Phase III and what we should think about as reasonable designs. That would be really helpful.

Yes. Thanks, Mani, for the question. Appreciate it. Maybe I'll kick it over to Doug to address this one.

So thank you for that question. It gets right at the root of the measure. And LGMD2i is a chronically progressive disease. And obviously, the need to demonstrate an early response is the biggest challenge in drug development in this space. We have upcoming FDA interactions that should be occurring in the second quarter that will help clarify their guidance and acceptability of our Phase III protocol design that we are proposing to them. At this point, we are proposing a double-blind randomized controlled trial that will look at a number of clinical measures, including ambulatory measures, specifically 10-meter walk, other clinical function measures, the NSAD, ventilatory measures such as forced vital capacity and upper-limb measures such as the PUL 2.0, all of which reflect important and meaningful aspects of the disease and the disease progression that's seen. So we're very excited to have these meetings upcoming in the second quarter, and that we'll have a lot more to say thereafter.

That's helpful. And if I have one quick follow up. So there's a few other players [ that are in the ] universe who are going after indications with profound unmet need, but fairly complex composite phenotypes. That's not uncommon in inherited systemic genetic disorders. Where are you in terms of sort of patient community engagement? And getting a little of feedback on what the patients are most concerned about given the broad constellation of symptoms halogen on this?

Yes. Doug, do you want to take that as well?

Yes, certainly. So we've had extensive conversations and continue to have active dialogue with a whole host of patient advocates, patients and members of the patient community in general. What you raised is really a critical aspect. This is a broad heterogeneous disease. There's impact across a wide array of clinical symptoms. And the feedback that we've received from patients is that while massive home-run type impacts are certainly welcomed and would be graciously and delightfully accepted, patients are looking for things that can even modestly improve the course of the disease, it's a disease that progresses over decades, but leads to ultimately or dependence in most patients and cardiac ambulatory and other quality of life impacts as well. And so even just slowing down the progression of the disease would be considered a major win in the minds of many of the patients. And certainly, I think there's a huge appetite and interest in the patient community to advance things from a symptomatic management to something much better. And they're hopeful and really interested and invested with us to move this program forward.

Our next question comes from the line of Salim Syed from Mizuho.

I'd also like to add my congratulations to the operator for the subject title at the beginning for the effort there. I guess a few for me, if I can, guys. One, I don't see the ADG results from day 90 to day 180 on the poster. So I'm wondering, is that something that wasn't measured between day 90 and day 180. Or maybe you could talk about the ADG results there? Secondly, I was wondering if you could speak to some of the baseline characteristics among the 3 cohorts and if there were any remarkable differences that could explain some of the results, which are not -- were not seeing a dose-dependent response. And then just lastly, just around when you're thinking about the Phase III -- and this is a follow up to Mani's question, when you think about the Phase III end point, are you thinking about 10-meter walk test here as a primary -- sole primary endpoint? Or is this going to be a composite? Because obviously, we're talking about 0.10 meters per second velocity change. So I imagine there's going to be some noise around this endpoint. So I'm just wondering if that's -- this is more of a primary or composite for the Phase III.

Yes. Thanks, Salim, for the questions. And thanks for the shadow to the operator agreed on LGMD2i pronunciation. All right. Well, let me send it over to Doug. We also have Marissa Lynn on the line, who is our -- who runs our BD and Ops for the program, so she might want to chime in on a few of these as well. But maybe I'll ask Doug to get started on these 3 and then we can circle back.

Yes. So I was still busy thinking about the third one. I'm blanking on the first one. I think the first question was related to the ADG assay and the timing of different results.

Yes, the day 90 to day 180, which I don't see the day 180 on the poster, yes.

Yes. We're -- the bioassay requires a little bit of additional work to get the results than clinical measures that are generally available in real time. And because of that, we don't have the full results yet of the ADG assay for day 180. So we're expecting that relatively soon, and we'll be very interested to present that at future meetings. I think the second question was regarding the differences between the cohort.

Yes, the baseline characteristics. Were there a remarkable difference there among 3 cohorts that you explained?

Exactly. So there's attempt to balance the cohorts to some degree with regard to the genetic profile as people deeply invested in the 2i community would be aware and everybody else would not. We do -- there's a common mutation that about 2/3 of patients have that has generally less severe disease progression than patients who are compound heterozygotes. And so we attempted to have that genetic profile balance as well as the ambulatory and non-ambulatory status balance. What ended up happening cohort 3 is somewhat older and has, I think, a greater degree of baseline disease progression when compared with the cohort patients in cohorts 1 and 2. We have full data on 12 of the 14 patients at this point, so we'll be continuing to provide information on the remaining 2 Cohort 3 patients who enrolled on the later side relative to their peers later this year to help further substantiate that dose response and drive dosing decisions thereafter. The third question was on choice of endpoints. And what you're hitting at is right at the core of how we're -- of a great deal of thinking that we've had at this point. We are looking at discussing the role of co-primary endpoints, looking at functional measures such as [indiscernible], and looking at 10-meter walk test. At this point, there's no perfect answer to that question, but we are very interested in discussing with the regulatory authorities our approaches, which will be to provide a strong totality of the evidence, and we do intend and expect to have ambulatory measures such as a 10-meter walk as a lead, if not the lead end point probably is our primary and lead endpoint in our clinical study.

Yes. Maybe just to build on that just because I know -- and this sort of goes to Mani's point as well. I mean we don't have full clarity as to what that final primary would look like, but we will be discussing everything from actually using Alpha DG and a surrogate for approval, just given how devastating this disease is and how proximal it is as a measure to the path of mechanism of the disease, all the way from that to establishing a primary associated with 10-meter walk time. But obviously, it would be hierarchical as you suggested, so just based on how you want to power something like this. So that would be my expectation is either you can get some sort of a surrogate or one would use a primary endpoint that was a hierarchical analysis of time a 10-meter walk time and then NSAD or something like that. So -- but to Doug's point, we really do need to engage with the regulators first to get more clarity on it. Maybe I'll ask Marissa actually to make a couple of comments on -- or George on how we've been engaging the KOL of patient community as well on this really important point of the basis of evidence for approval.

Yes. Thank you, Neil. This is Marissa speaking. And I think we have strong ties with the patient community. I mean this is a really active community as well. We've engaged with patient advocacy leaders and patients together and focus groups to really bring the patient voice to light in our future plans. And I think as Doug mentioned to you earlier, when we talk to patients, what they say is, given that it's a slowly progressive disease, the number one piece that they would like to see is a slowing of that progression for the disease. They also mentioned functional components, say, like being able to get up from the toilet as particularly important to them as well. So I think it's something that we're working together hand in hand as we move through our clinical development program living by the BridgeBio kind of code of ethos to bring that patient voice to light.

Our next question comes from the line of Tom Shrader from BTIG.

Congratulations on the data. I guess I have a simple question. Do you think you need to try lower doses? You didn't give any dose dependence for your safety. And as far as I can tell, it looks like all the doses are the same. Do you think you need to try lower doses? Or do you think you have what you need?

Thanks, Tom, for the question. Yes, maybe I'll kick that over to Doug and Marissa.

Yes, so I'll talk and then ask Marissa to dig off a little bit. But I think one of the basic premises, which is not always correct, but I think is a very reasonable one in this state is that the highest levels that we can provide within the bounds of safety are most likely to have the greatest impact. We know from the animal models that there was a dose response that was seen in lower-dose animals having a less robust response compared to animals that received a higher dose. And so there is evidence from the animal models of a dose response. A small study such as we presented is probably insufficient to really firmly establish that. But what we are operating upon is a basic premise that based on what we've seen from the preclinical data, based on the strong safety profile that we've seen thus far across all the dose ranges that providing a dose up in the dose of 12 grams twice a day will offer us the opportunity to achieve drug exposure in the cells in patients that is within that high therapeutic range that we saw in the animal models, and it's the most likely to give the most robust clinical response. Marissa, you have additional color?

Yes, I would just add a little bit of color as to how the specific dose levels were selected for the Phase II. So that low dose cohort 1, which was the 6 grams daily, we picked that because that was just at the lower edge of where we started to see efficacy in the mouse model and 12-gram CIB was at the upper edge. So our hypothesis going into it that, that low dose would be just at the lower level to see efficacy. And so we were extremely pleased when we started to see robust responses even at that low dose. The one other thing I would mention as well that there are ongoing studies to further understand the kinematics of the FKRP enzyme itself. I mean I think that will allow us to further make decisions around the correct dose going forward.

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

Congrats on the data. I have a clarification point along the lines of the prior 3 questions. But is it the 12 mg BID dose that you'll be taking into pivotal or at least based on Marissa's last comments, that it seems like you might be doing a little bit more work on them dosing to a selection for the pivotal? And how much of that Part 2 max dose 12 mg BID data will you have in hand as you engage with regulators in 2Q?

Thanks, Anupam. I'll kick it over to Doug again, yes.

So yes, so we feel comfortable at this point with the dose selection of 12 grams twice a day. There is a dose schedule for low-weight patients that we have derived from our ongoing PK data that we've accumulated across the well over 100 patients that have been treated at this point or individuals have been treated at this point. The -- and so we intend to proceed into Phase III with the 12-gram twice a day dosing. The other question was related to the Phase II data that we expect to have available. We do expect to have additional data through 6 months and -- in case cohort 1 and to some degree, cohort 2 through 9 months of clinical data at the time that we're engaging a regulatory counterparts, and we hope and expect that, that additional increasingly mature data will further substantiate our position as we engage the regulators.

Our next question comes from Paul Choi from Goldman Sachs.

I want to maybe circle back to the assay for a moment here. And just can you maybe comment on a few things. First, I think a year ago at this meeting, you presented a Western blot on Type 2 limb-girdle patients. And can you maybe just speak to how well that your assay correlates with that Western data, blot data? And then second, it sounds like you guys might be tweaking the assay a little bit. Where are you on that? Or how close is it to its final form? And then any commentary on -- from the regulators with regard to the acceptability of the assay at this point? Or is this something you plan to discuss in your pre-Phase III meeting? And then my second question was with regard to both the biomarker and functional outcomes, can you speak as to any differences among the responses by mutation type? And would that potentially or prospectively define the population you would focus on in your Phase III.

Thanks, Paul. Great questions. We don't have Uma on the line to speak to all the assay technical issues. But maybe I'll ask Marissa to kick it off on the assay comments, and then we can move to the second question.

Great. Yes, I can talk about the assay. So you're absolutely correct. Last year, we presented data at MDA, establishing baseline values and genotypic relationships showing that in this disease, heterozygous had the lowest level of baseline alpha-dystroglycan and then homozygous had a higher level of baseline ADG, which correlates to known differences in severity between those 2 groups. That initial assay that was presented, we have been making improvements in order to push that assay into a Phase III readiness form. This is something we're looking to actively engage with regulators in upcoming meetings to understand the potential for this assay and biomarker going forward. I think the second question you asked was about known differences based off of genetic type within this population and how that may potentially impact selection of patients for ongoing trials. And I think I'll hand that over to Doug to comment on.

Yes, it's a very good point that you raised. We know from established natural history data sets and from clinical experience that patients who have a -- have the L276i common mutation, it's a founder mutation that is seen in what we call homozygotes in approximately 60% of patients, with the remainder being compound heterozygotes, usually 1 L276i mutation and 1 other mutation. And these populations act as a group very differently on patients who are compound heterozygotes tend to present earlier and have a more severe disease course. And this probably represents -- it starts to represent a reduced enzyme activity in that second mutated FKRP gene. We are planning on stratifying our Phase III study to ensure a balance of compound heterozygotes. And L276i homozygotes patients across the 2 study cohorts. But we do expect that as long as there is some residual enzyme activity -- and that is probably necessary for function survival anyway, but as long as there's some degree of enzyme activity, we do expect that there is a premise and a prospect of having a therapeutic response to this therapeutic strategy.

Okay. Maybe just to clarify, just with regard to the status of the assay, would you say you're middle innings, late innings of getting to its final form before you go to the regulators? And just on the data itself that you presented today, can you maybe speak to differences, if any, between the subtypes in terms of either the biomarker or the functional end points?

Yes. So Marissa do you want to take that -- go ahead, Doug.

Yes. I think we're in the middle of the late innings to use your baseball analogy in regards to having the assay ready for Phase III, and that's certainly something that will be top of mind when we engage with regulators in the upcoming months. So it should be something that will be certainly ready as we look to move forward into Phase III shortly. And do you also...

Doug, do you want to answer the second part? Yes.

So can you repeat the second part, because it got a little -- can you just mind repeating that question?

Yes, sure. And I was just curious if you had cut the data in terms of the -- either the biomarker or functional endpoints by mutation subtype and if you're seeing any differences between heterozygous and homozygous -- excuse me, in the data you've presented today?

So we've looked at -- so at this point, we have data on heterozygous patients and on homozygous patients, both for the ADG assay as well as for CK. And we are seeing a response in homozygous patients, we are seeing a response in heterozygous patients, both as measured using our ADG glycan to total ADG assay as well as in the secondary marker creatine kinase. So we don't have enough data at this point to say whether there's more of a response in one population versus another. But we are seeing a response across the entire cohort.

Our next question comes from Ellie Merle from UBS.

Just in terms of the natural history data, maybe, I guess, from some of the data on the compound heterozygous, I guess how much do we know about how much a shift in the enzyme level ratios could modify the clinical course of the disease? And I guess, just kind of coming back to the potential use of biomarkers or a surrogate, I guess how validated is the sort of enzyme ratio level at the surrogate marker in the disease? And can you just kind of elaborate on what the key data sets are that could support this, if so? And then kind of a follow-up question. Just you mentioned kind of the potential for expansion in other indications. Could you just elaborate there and talk a little bit about the biology and potential opportunity set longer term?

Yes. Maybe I'll kick that one over to Marissa to start and then Doug, we've talked a lot about what the bar looks like in terms of Alpha DG increases and the evidence for it.

Yes, it's a great question. What we've seen based off of previous work is about a 10% to 20% difference between hets and homs. So the idea is that as we established early in the call, that 10% increase could move you from a heterozygote trajectory where you have an earlier age of onset and a more severe disease trajectory to more of a homozygous trajectory. And similarly for homozygous, you could bump those patients up to a more normal course of disease state. So that's something that we've seen based off of -- you're asking the data sets we have available. So we have that preliminary data set that we presented at MDA last year. We have mouse model data. And then we do have a large 100-plus patient natural history trial going on, where we have longitudinal ADG samples from these patients, and we'll be looking on further explore this correlation between genotype and baseline ADG level with the additional data that comes from that natural history data set, and that's something we'll be looking to present at additional neuromuscular conferences throughout the year. I think I can pass it to Doug, if you have any other additional comments.

Yes. So just to further reinforce what Marissa just said. When we talk about the -- when we talk about a 10% to 20% difference between compound heterozygous patients and patients with the L276i common mutation homozygous for that mutation, the clinical trajectory and difference between those 2 populations is quite stark. So patients who are compound heterozygous wind up being wheelchair dependent on average around age 20, which is a couple of decades earlier than patients who are compound -- or who have the L276i common mutation. And so making that sort of 10% to 20% shift could have -- if you were able to transition somebody from being -- having a phenotype consistent with a heterozygous genetic makeup to a homozygous makeup, you've made a substantial clinical impact quite dramatic. So that's the one thing we'd like to emphasize there.

Next question comes from Dane Leone from Raymond James.

Congrats on the data update. Two easy ones on my end. Could you please comment to the GI disturbance for these patients and whether there was tolerability built up as dosing went on as in was this a transient GI disturbance? Or was this something that was continuous in certain patients? And then the second question is when you think about functional assessment endpoints that the regulators could ask you for, do you currently have enough natural history data on something like the limb-girdle adapted version of the north star test to understand what the control would have to be powered to for expected outcomes at whatever functional time point you need?

Yes. Thank you for the question. So related to the first one, which is the side effects that we've seen thus far in our Phase II study. As I mentioned, there were 8 low-grade adverse events, all GI in nature that we're seeing. In discussion with the investigator, what we have -- what seems to have occurred is that most of these events occurred in patients who were taking the drug without food right after -- right upon starting the drug. These were all self-limited, and in most cases, appear to have completely resolved by switching that up and taking the drug concurrently with food, which is something that we've established as reasonable and appropriate. And so all these are self-limited. We're actually very interested in seeing if that completely solves the issue going forward. But certainly, even if it doesn't, this is something that is not seen as dose limiting or impacting the uptake of this product in use in patients. Regarding the second one, Marissa, do you want to comment on that?

Yes, I can comment. Asking about north star data from natural history and if that will be sufficient to make powering assumptions. And I would say, yes. As I mentioned previously, we had this 100-plus patient natural history study ongoing with a year plus worth of data, where we've been able to quantify rates have changed annually across a number of endpoints, north star being one of them. And I think based off of that data set, we will be able to understand powering assumptions for our Phase III trial.

Our next question comes from Greg Harrison from Bank of America.

This is Mary Kate on for Greg. So you are also planning to present Phase I data 418 in healthy patients. Maybe what could the Phase I healthy patient study tell us about the LGMD2i story.

Can I take that?

Yes, thanks for the question. Doug? Yes, please do.

So yes, thank you for bringing that up. We are concurrently presenting that data as well at the MDA meeting. And so kind of swept that aside and around our excitement around our Phase II study. To summarize our Phase I data, what we've explored a wide range of doses in both a single ascending dose format as well as a multiple ascending dose format. We've -- what we've seen is a strong striking linearity and relationship between the exposure and the dose level. So doubling a dose doubles the exposure. We've seen a consistent relationship between the dose bridging the pharmacokinetics and the single ascending dose versus the multiple ascending dose. And so there's a very simple pharmacokinetics that's going on here. And we were able to dose patients up to 15 grams in the single ascending dose format. We dosed patients up to 9 grams in the multiple ascending dose format with minimal adverse events seen across the entire dosing cohorts within the context of that study. We also performed a food effect study, actually, 2 of them, the higher one at the 12-gram twice a day dosing to establish an equivalence there. So we've had a remarkably unremarkable Phase I study that puts us in an extremely good place as far as our understanding of this product as we move into our clinical studies in patients. Marissa, do you have any other color you want in there?

Yes. The only other comment that I would add is the Phase I and the Phase II really support each other in regards to the safety profile for this agent. And I think it really sets ribitol apart, especially when you compare it to other potential therapeutics in development here being gene therapy. I think the fact that it's oral and only minor GI-related adverse events which purely -- that were transitive in nature, really give us home one of the big advantage is for BBP-418.

Our next question comes from the line of Ram Selvaraju from HCW.

Just wanted to see if you could touch upon 3 areas. Firstly, from a regulatory as well as patient and prescriber perspective, what do you anticipate is likely to be the optimum time frame within which you would need to demonstrate longitudinal efficacy of 418 hypothetically in the pivotal context? Secondly, if you can talk a little bit about the concept of stopping deterioration versus inducing improvement and how that fits into the positioning of 418 as a therapy given its mechanism of action and what you think is reasonably likely to be achievable here? And then lastly, if we think about patient selection in the context of a pivotal program, if you can maybe elaborate upon which of the cohorts in this study is most likely to be replicative of the ultimate Phase III patient population.

We'll ping pong. I'll ask Marissa to chime in on what I missed here. The first question is related to the duration of study, I think, is the key question. What you raise is some of the critical balancing that we need to impart, the need to do a study of sufficient length and sufficient robustness to meet that critical obligation that we have to demonstrate the effectiveness of this therapy to the regulatory authorities, to payers and others. And certainly, the other is balance the need of the patient community to get these studies done as quickly as possible with this limited impact as needed burden on patients. We've spoken to a whole host of different stakeholders and the general guidance is study at the bare minimum needs to be at least 12 months, probably longer. I think what we have been in discussions with is looking at around 12 to 24 months, where we have our upcoming regulatory interactions. And we have a -- we'll have more to say once we've received their guidance on duration of therapy. The second was related to the question of what is a meaningful impact, and what is underlying a potential improvement in the clinical measure. So I've answered it in kind of 2 ways. One is that if you're able to reverse the cellular phenotype and you're able to interrupt the ongoing dystrophic processes and the breakdown of muscle, there's a prospect for some -- there's a prospect of recovery. And so the premise that patients might actually get better with an effective therapy is not magical thinking. It's not outside the realm of what you might expect. That said, it's also beyond what would be considered beneficial to the clinical -- or to the patient community. And so while we're very excited to see some early signals of actual improvement in patients relative to their baseline, we don't consider that as something that is necessary for a therapy, especially one of this nature to be something that would be a valued part of the therapeutic arm of inherent and then be very welcome by patients. The third question was how representative patients are for the various cohorts. Marissa, do you want to comment on that?

And I can take that. What I would like to say here, I think potentially a better way to think about this is since we do have this natural history study going, that's going to be a huge source of enrollment for the Phase III trial. So the composition of the Phase III trial is going to be most similar to the composition of that lead-in study, which will have more information available that later in the year. But what I can say is that we enrolled both homs and hets with similar distribution to the larger patient population, which is about 2/3 homozygotes and 1/3 heterozygous. We enrolled both adults and pediatric patients in that study. So we'll be looking to incorporate both in our Phase III as well as low and high functioning patients. So I think more to come there, but the natural history will be the largest source of patients for that trial and likely to have similar composition.

There are no further questions at this time. I'll now turn the call back to Mr. Neil Kumar for closing remarks.

Okay. Well, thank you, everyone, for the time and for the questions, and we look forward to advancing this program as well as our broader pipeline and to take all of the questions as they may arise in other forms as we progress. Thanks again.

That does conclude our conference for today. Thank you for participating. You may all disconnect.