Good day, and thank you for standing by. Welcome to the BridgeBio Pharma conference call to discuss phase II data for BBP-418 in limb-girdle muscular dystrophy type 2I. At this time, all participants are in a listen-only mode. After the speakers' presentation, there will be a question and answer session. To ask a question during the session, you will need to press star one on your telephone. Please be advised that today's conference is being recorded. If you require any further assistance, please press star zero. Now I'd 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 disease, limb-girdle muscular dystrophy type 2I. Before we begin, I just wanna 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 wanna take a quick moment and introduce the leader of our efforts in LGMD 2I, Dr. George McLendon.
As you can see, he has a very long story. He's been a chemistry professor, a PhD, Chairman of the Department of Chemistry at Princeton, and Dean of Arts and Sciences at Duke University. He's also co-founded six various startups in genetic diseases and elsewhere, four of which have had exits. 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. 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 at 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 was founded actually by patient families to serve patients and their families. Through the McColl-Lockwood Lab, which is at Atrium Health. Dr. Qi Lu at the McColl-Lockwood Lab developed an idea that the FKRP mutation, which lies at the heart of LGMD 2I, might be rescued if you could supplement the substrate at high enough concentrations to force the substrate to bind and therefore force the enzyme back to work. That idea turned out in a syngeneic mouse model to work. The next question was: how do we stop curing mice and start curing people? For that, we needed a partner.
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. What was so exciting to us about BridgeBio was that they had built in expertise that could enable us to move much more quickly. I'm excited today to be able to say that less than three years after we started, we're now able to report what I believe is very exciting phase II data. We'll be in phase III shortly thereafter. That's sort of the timeline. For those of you who know drug development, moving that fast from a Nature paper to phase III is really something. Let's just move to what is LGMD 2I. Next slide, please.
Type 2 I 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. If the enzyme FKRP can't make that polymer, then your muscle cells become much weaker, much less stable. BBP-418, the drug that we're using, is in fact a substrate for FKRP. 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.
As you'll see with this agent, which is first in class as a disease-modifying agent, should be first treatment to be approved, we hope. Has some excellent safety and efficacy alongside really simple oral dosing. Everything about this agent, I've been involved in developing other drugs, this is a truly remarkable one. 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. If you go to slide six, 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. On the next slide seven, BBP-418 or ribitol is being investigated as an upstream substrate to drive this residual activity of the mutant enzyme.
The alpha-dystroglycan protein is glycosylated, meaning that there are sugars that are attached to it, and one of the sugars is ribitol. 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 the FKRP enzyme, then the ribitol is not really attached properly. The aim of the therapy is to provide more of the ribitol, and it's orally administered. That way, you can actually help the alpha-dystroglycan bind to other proteins and produce more normal function. If you go to the next slide eight, we have a full part one and partial part two data available from phase II. In part one, there was a dose escalation.
There were 14 participants over a period of 90 days, and there are three different dose levels as you can see. There's 6 grams daily, 6 grams twice a day, and 12 grams twice a day. In part two, everybody was escalated to the maximum dose. There are three key study objectives. Safety and tolerability, dose selection for the subsequent phase III, and key biomarker parameters. There were six key endpoints. Creatine kinase, the ratio of glycosylated alpha-dystroglycan, the total alpha-dystroglycan, the North Star Assessment for dystrophinopathy, the PUL 2.0, a 10-meter walk test, and a forced vital capacity. I will now hand it over to Dr. Sproule.
Hi, good morning. Thank you for the excellent overview, Dr. Kang. If you go to slide 10, this just summarizes what I'm gonna talk about over the next couple slides thereafter. I wanna kinda level set as far as what we would expect, and I'll talk more about our αDG glycosylation assay in just a second, as well as the role of creatine kinase. Just to kinda level set what we would expect. Alpha-dystroglycan should be fully glycosylated in a healthy state. What we would expect is that if you took a ratio of the proportion of glycosylated αDG to total αDG, that ratio should be in the vicinity of one.
we see in LGMD 2I 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 our animal data is that at least a 10% increase in that ratio would be necessary to drive a phenotypic change. I'll talk more about the results in a second. What we see early on from our phase II study is over 40% increase from baseline on average in the αDG 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. Generally, a level 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. We're seeing well over a 70% decrease from baseline.
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. What we would like to see in a therapeutic effect, effective therapy is at least a slowing of that decline. What I'll talk about with our 10-meter walk test results thus far, they're early results, but they actually suggest an improvement in clinical function from baseline. 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 eight, all low grade, are deemed to be possibly or probably related to therapy.
These are self-limited gastrointestinal manifestations, which is not surprising, 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 αDG as a proportion of the total amount of αDG within muscle tissue. We call this the αDG glycan to total αDG ratio. We previously showed that samples from untreated patients with LGMD2I have reduced fully glycosylated αDG when compared with healthy control tissues. An effective disease-modifying therapy for LGMD2I that addresses the root cause of the disease, which is defective and deficient glycosylation of αDG, would be expected to increase that ratio of fully glycosylated αDG, ideally towards the levels that are seen in healthy tissues.
Here we show that an average increase of more than 40% is across all three cohorts in the αDG glycan to total αDG ratio is 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.
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 serum CK levels. In our phase II study, we 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, you know, in a disease-modifying therapy, we do see a nice correlation between increases in αDG glycosylation and 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 three dosing cohorts. You can see that in the three solid spaghetti plot lines in the figure on the left. This contrasts nicely with the decline in walking speed that was seen over the six months prior to starting therapy in those same patients.
You see that trajectory projected in the dotted lines on the figure, showing a separation between 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're very interested to see how patients are six, nine, 12 months after initiation of therapy. Moving to slide 16, to summarize what I just talked about, we presented the phase II part one and partial part two data. This has showed a 43% increase in the ratio of glycosylated alpha-dystroglycan to total alpha-dystroglycan, and approximately 70% reduction in creatine kinase from baseline at Day 90, and 77% reduction at Day 180 following therapy.
We've seen improvements in functional benefits observed 90-day, 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. 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.
We are very excited to have for our upcoming interaction 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. With that, 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.
Thank you. As a reminder, if you wish to ask a question, please press star one on your telephone and wait for your name to be announced. If you wish to withdraw your request, please press the pound or hash key. Once again, it's star one for questions. Our first question comes from the line of Mani Foroohar from SVB Securities. Please ask your question.
Hey, guys. Thanks for taking the question. Can you give us a sense of where you are in your previous discussions with regulatory authorities? More broadly, how should we 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 phase III, and what we should think about as reasonable designs, that'd be really helpful.
Yeah. Thanks, Mani, for the question. Appreciate it. Maybe I'll kick it over to Doug to address this one.
Yeah. Thank you for that question. It gets right at the root of the measure. 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. We're very excited to have these meetings upcoming in the second quarter, and that'll. We'll have a lot more to say thereafter.
That's helpful. If I have one quick follow-up. There's a few other players in our 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 feedback on what the patients are most concerned about given the broad constellation of symptoms pathology in this illness?
Yeah. Doug, you wanna take that as well?
Yeah, certainly. 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 raise is really a critical aspect. This is a broad heterogeneous disease. There's impact across a wide array of clinical symptoms. What 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. This is a disease that progresses over decades that leads to ultimately wheelchair dependence in most patients and cardiac, pulmonary, and other quality of life impacts as well.
Even just slowing down the progression of disease would be considered a major win in the minds of many of the patients. 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. They're hopeful and really interested and invested with us to move this program forward.
Great. Thanks for taking the question, guys.
Thank you. Our next question comes from the line of Salim Syed from Mizuho. Please ask your question.
Great. Good morning, guys. Thanks for the color, and I'd also like to add my congratulations to the operator for the subject title at the beginning for the effort there. I guess, like, a few for me, if I can, guys. One, I don't see the αDG results from Day 90 to Day 180 on the post. So I'm wondering, is that something that wasn't measured between Day 90 and Day 180, or maybe you could talk about the αDG results there? Secondly, I was wondering if you could speak to some of the baseline characteristics among the three cohorts and if there were any remarkable differences that could explain some of the results, which we're not seeing a dose-dependent response.
Just lastly, just around when you're thinking about the phase III, and if this is a follow-up to Mani's question, when you're thinking about the phase III endpoint, are you thinking about 10-meter walk tests here as a primary, sole primary endpoint, or is this gonna be a composite? 'Cause you know, obviously we're talking about you know, 0.10 meters per second velocity change. Imagine there's gonna be some noise around this endpoint. I'm just wondering if this is more a primary or composite for the phase III. Thank you.
Yeah. Thanks, man, for the questions. Thanks for the shout-out 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 runs our BD and Ops for the program. So she might wanna chime in on a few of these as well. But maybe I'll ask Doug to get started on these three, and then we can circle back.
Yeah. I was so busy thinking about the third one. I'm blanking on the first one. I think the first question was related to the αDG assay and the timing of different results.
Yeah. The Day 90 to Day 180, which I don't see the Day 180 on the post right here.
Yeah. The bioassay requires a little bit of additional work to get the results than clinical measures that are generally available in real time. Because of that, we don't have the full results yet of the αDG assay for Day 180. 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.
Baseline. Yeah, the baseline characteristic. Were there remarkable differences among the three cohorts that could explain?
Exactly. There's an 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. There's a common mutation that about 2/3 of patients have that has a generally less severe disease progression than patients who are compound heterozygotes. We attempted to have that balance, the genetic profile balanced as well as the ambulatory and non-ambulatory status balanced. What ended up happening, cohort three is somewhat older and has, I think, a greater degree of baseline disease progression when compared with the cohort patients in cohorts one and two.
We have full data on 12 of the 14 patients at this point, so we'll be continuing to provide information on the remaining two cohort three 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. You know, what you're hitting at is right at the core 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 the NSAD 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. We do intend and expect to have ambulatory measures such as a 10-meter walk as a lead, if not, as a lead endpoint, probably as our primary and lead endpoint in our clinical study.
Got it. Thank you much for the clar-
Yeah. Maybe just to build on that, just 'cause I know, this sort of gets to my point as well. I mean, you know, 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 as 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 a 10-meter walk test. But obviously it would be hierarchical, as you suggest, Salim, just based on, you know, how you want to power something like this.
That would be my expectation is, you know, either you can get some sort of a surrogate or, one would use a primary endpoint that was a hierarchical analysis of 10-meter walk time and then, you know, NSAD or something like that. But to Doug's point, we really do need to engage with the regulators first, to get more clarity on it. Maybe ask Marissa actually to make a couple comments on, or George, on how we've been engaging the KOL or patient community as well on this really important point of the basis of evidence for approval.
Thank you, Neil. This is Marissa speaking. I think we have strong ties with the patient community. This is a really active community as well. We've engaged with patient advocacy leaders and patients together in focus groups to really bring the patient voice to light in our future plans. I think as Doug mentioned too 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 to forestall disease. They also mentioned functional components, say, like being able to get up from the toilet as particularly important to them as well.
I think, you know, it's something that we're working together hand in hand, as we move through our clinical development program, you know, living by the BridgeBio kind of patient direct ethos, to bring that patient voice to light.
Super helpful. Thanks so much, guys.
Thank you. Our next question comes from the line of Thomas Shrader from BTIG. Please ask a question.
Good morning. Congratulations on the data. I guess I have a simple question. Do you think you need to try lower doses? You didn't get any dose dependence for your safety. 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. Yeah, maybe I'll kick that over to Doug and Marissa.
Yeah. I'll talk and then we'll ask Marissa again after a little bit. I think one of the basic premises, which is not always correct, but I think it's 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. 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.
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 most likely to give the most robust clinical response. Marissa, you have additional color?
Yeah. I would just add a little bit of color as to how the specific dose levels were selected for the phase II. That low dose cohort one, 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. 12 grams BID was at the upper edge. It was our hypothesis going into it that that low dose would be just at the lower level to see efficacy. We were, you know, extremely pleased when we started to see robust responses even at that low dose. You know, the one other thing I would mention as well is that there are ongoing studies to further understand the kinematics of the FKRP enzyme itself.
I think that will allow us to, you know, further make decisions around the correct dose going forward.
Okay. Great. Thank you.
Thank you. Our next question comes from the line of Anupam Rama from JP Morgan. Please ask your question.
Hey, guys. Thanks so much for taking the question, and congrats on the data. I have a clarification point along the lines of the prior three questions. 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 the dosing dose selection for the pivotal. How much of that part two max dose 12 mg BID data will you have in hand as you engage with regulators in 2Q? Thanks so much.
Thanks, Anupam. Doug, kick it over to Doug again. Yep. 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 well over 100 patients or individuals that have been treated at this point. 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 six months and in some cohort one and to some degree cohort two through nine months of clinical data at the time that we're engaging our regulatory counterparts. We hope and expect that additional increasingly mature data will further substantiate our position as we engage the regulators.
Thanks so much for taking our question.
Thank you. Our next question comes from the line of Paul Choi from Goldman Sachs. Please ask your question.
Hi. Thanks, Neil. Good morning, everyone. 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 and on type 2I limb-girdle patients. Can you maybe just speak to how well your assay correlates with that western blot data? Then second, you know, it sounds like you guys might be tweaking the assay a little bit. You know, where are you on that or how close is it to its final form? Then any commentary on from the regulators with regard to the acceptability of the assay at this point?
Is this something you plan to discuss in your pre-phase III meeting? My second question was, with regard to you know, both the biomarker and functional outcomes, can you speak as to any differences among the responses by mutation type? Would that you know, potentially 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 comment, and then we can move to the second question.
Great. Yeah. I can talk about the assay. You're absolutely correct. Last year, we presented data at MDA, establishing baseline values and genotypic relationships showing that in this disease, heterozygotes had the lowest level of baseline alpha-dystroglycan, and homozygotes had a higher level of baseline αDG, which correlates to known differences in severity between those two groups. That initial assay that was presented, we have been, you know, 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 as a 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. I think I'll hand that over to Doug to comment on.
Yeah. It's a very good point that you raise. We know from established natural history data sets and from clinical experience that patients who 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 one L276I mutation and one other mutation. These populations act as a group very differently. Patients who are compound heterozygotes tend to present earlier and have a more severe disease course. This probably represents 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 homozygous patients across the two study cohorts. We do expect that as long as there is some residual enzyme activity and that is probably necessary for function survival anyway. As long as there's some degree of enzyme activity, we do expect that there's a premise and a prospect of having a therapeutic response to this therapeutic strategy.
Okay. Maybe just to clarify, just with regards to the status of the assay, would you guys say you're middle innings, late innings of getting to its final form before you go to the regulators? 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 endpoints?
Yeah. Marissa-
I think.
Oh, go ahead, Doug.
Yeah. 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. That's certainly something that'll be top of mind when we engage with regulators in the upcoming months. It should be something that will be certainly ready as we look to you know move forward into phase III shortly.
Great.
And do-
Doug, do you wanna take the second part?
Yeah.
Go ahead. Can you repeat the second part? 'Cause it got a little. Can you just mind repeating that question?
Yeah, sure. I was just curious if you had cut the data in terms of either the biomarker or functional endpoints by mutation subtype, and if you're seeing any differences between heterozygotes and homozygotes in the data you've presented today.
At this point, we have data on heterozygous patients and on homozygous patients, both for the αDG assay and as well as for CK. We are seeing a response in homozygous patients. We are seeing a response in heterozygous patients, both as measured using our αDG glycan, total αDG assay, as well as in the secondary marker creatine kinase. We don't have enough data at this point to say whether there's more of a response in one population versus another. We are seeing a response across the entire cohort.
Okay. Great. Thanks for taking our questions, and congratulations on the data.
Thanks, Paul.
Thank you. Our next question comes from Ellie Merle from UBS. Please ask your question.
Hey, thanks so much for taking the question. Just in terms of the natural history data, maybe I guess from some of the data on the compound heterozygotes, 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, you know, the potential use of biomarkers or a surrogate, I guess how validated is this sort of enzyme ratio level as a 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, and other indications.
Could you just elaborate there and talk a little bit about the biology and potential opportunities at longer term? Thanks.
Yeah. 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, so and the evidence for it.
Yes. This is a great question. You know what we've seen based off of previous work is, you know, about a 10%-20% difference between HETs and HOMs. So the idea is that, you know, 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 homozygote trajectory. Similarly for homozygotes, you could bump those patients up to a more normal course of disease state. So that's, you know, that's something that we've seen based off of you're asking the datasets we have available. So we have that preliminary dataset that we presented at MDA last year.
We have mouse model data, and then we do have a large 100+ patient natural history trial going on, where we have longitudinal αDG samples from these patients. We'll be looking forward to, you know, further explore this correlation between genotype and baseline αDG levels with the additional data that comes from that natural history dataset, 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.
Yeah. Just to further reinforce what Marissa just said, you know, when we talk about a 10%-20% difference between compound heterozygous patients and patients with the L276I common mutation, homozygous for that mutation, the clinical trajectory and difference between those two populations is quite stark. Patients who are compound heterozygotes wind up being wheelchair dependent on average around age 20, which is a couple decades earlier than patients who have the L276I common mutation.
Making that sort of, you know, 10%-20% shift would 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. That's the one thing I would like to emphasize there.
All right. Great. Thanks for the color.
Thanks, Ellie.
Thanks. Next question comes from Dane Leone from Raymond James. Please go ahead.
Hey, thanks for taking the questions. Congrats on the data update. Two easy ones on my end. Could you please comment on the GI disturbance for these patients and whether there was tolerability built up as dosing went on? As in, you know, was this a transient GI disturbance, or was this something that was continuous in certain patients? 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? Thank you.
Yeah, thank you for the two questions. 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 eight low-grade adverse events, all GI in nature, that were seen. In discussion with the investigator, what seems to have occurred is that most of these events occurred in patients who were taking the drug without food right upon starting the drug. These were all self-limited and in most cases appeared 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. All these are self-limited.
We're actually very interested in seeing if that completely solves the issue going forward. Certainly even if it doesn't, this is something that is not seen as dose limiting or impacting the uptake of this product and use in patients. Regarding the second one, Marissa, do you wanna comment on that?
Yeah. I can comment. Asking about North Star data from natural history and if that would be sufficient to make powering assumptions. I would say yes. As I mentioned previously, we have this 100+ patient natural history study ongoing with you know a year plus worth of data where we've been able to quantify rates of change annually across a number of endpoints, North Star being one of them. I think based off of that dataset we will be able to understand you know powering assumptions for our phase III trials.
Thank you.
Thank you. Our next question comes from Greg Harrison from Bank of America. Please ask your question.
Good morning. This is Mary Kate on for Greg. Thanks for taking our question today. You are also planning to present phase I data, BBP-418 in healthy patients. Maybe what could the phase I healthy patient study tell us, about the LGMD2I story?
Neil, can I take that?
Yeah, please do.
Yeah, thank you for bringing that up. We are concurrently presenting that data as well at the MDA meeting.
Kind of swept that aside and get around our excitement around our phase II study. To summarize our phase I data, what we've explored are a wide range of doses in both a single ascending dose format as well as a multiple ascending dose format. What we've seen is a strong striking linearity and relationship between the exposure and the dose level. Doubling a dose doubles the exposure. We've seen a consistent relationship between the pharmacokinetics and the single ascending dose versus the multiple ascending dose. There's a very simple pharmacokinetics that's going on here. 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 two of them, the higher one at the 12-gram twice-a-day dosing to establish an equivalence there. We've had a remarkably unremarkable phase I study that puts us in extremely good place as far as our understanding of this product as we move into our clinical studies in patients. Marissa, you have any other color that you want in this?
Yeah. 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. You know, I think it really sets ribitol apart, especially when you compare it to other potential therapeutics in development here, being gene therapy. You know, I think the fact that it's oral and only minor GI related adverse events that were purely that were transient in nature really hammers home one of the big advantages for BBP-418.
Great. Thank you. Our next question comes from the line of Ram Selvaraju from H.C. Wainwright. Please go ahead.
Hi. Thanks very much for taking my questions. Just wanted to see if you could touch upon three areas. Firstly, from a regulatory as well as a patient and prescriber perspective, what you anticipate is likely to be the optimum timeframe within which you would need to demonstrate longitudinal efficacy of BBP-418, you know, 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 BBP-418 as a therapy given its mechanism of action and what you think is reasonably likely to be achievable here.
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? Thank you.
Those are all great.
Yep, go ahead.
We'll ping-pong. I'll ask Marissa to kinda chime in on what I miss here. The first question is related to the duration of study, I think is the key question. What you raised 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. Certainly the other is to balance the need of the patient community and to get these studies done as quickly as possible with as limited impact as needed, burden on patients.
We've spoken to a whole host of different stakeholders, and the general guidance is the study at the bare minimum needs to be at least 12 months, probably longer. I think what we've been in discussions with is looking at around 12-24 months, where we have our upcoming regulatory interactions. We will 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 a clinical measure. I'd answer it in kinda two 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 of recovery. 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. 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 armamentarium and be very welcomed by patients. The third question was how representative patients are for the various cohorts. Marissa, do you wanna comment on that?
I can take that. You know 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. The composition of the phase III trial is going to be most similar to the composition of that lead-in study, which we'll have, you know, more information available later in the year. You know, what I can say is that, you know, we enrolled both HOMs and HETs with similar distribution to the larger patient population, which, you know, is about 2/3 homozygotes and one-third heterozygotes.
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. I think, you know, more to come there, but the natural history will be the largest source of patients for that trial and likely to have similar composition.
Thank you.
Great. Thank you. 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 your questions as they may arise, in other forums as we progress. Thanks again.
Thank you. That does conclude our conference for today. Thank you for participating. You may all disconnect.