BridgeBio Advancing Therapy for Limb-Girdle Muscular Dystrophy that Started with Two Patient Families

Limb-girdle muscular dystrophy type 2i is a rare, genetic condition that causes progressive muscle degeneration that can impact skeletal, respiratory, and cardiac muscles. As the condition progresses, people lose the ability to perform routine daily activities, such as walking or standing up without assistance. There are no therapies available today to slow, halt, or reverse the condition. ML Bio, a company founded by two patient families in search of treatments for the condition and later acquired by BridgeBio, is advancing an experimental therapy with the potential to become the first oral treatment for the limb-gridle. We spoke to Doug Sproule, chief medical officer of ML Bio Solutions, about limb girdle muscular dystrophy type 2i, the company’s experimental therapy to treat the condition, and the power of rare disease patient families to shape drug development. One note before we begin. Early in the discussion Sproule misspeaks. The founders of ML Bio are the McColl and Lockwood families and the company’s lead experimental therapy was discovered at the McColl-Lockwood Lab.

Daniel Levine: Doug, thanks for joining us.

Doug Sproule: Hi. It’s my pleasure. This is great to be able to talk today.

Daniel Levine: We’re going to talk about limb-girdle muscular dystrophy, ML Bio Solutions, and it’s experimental therapy to treat the condition. Before we do that, though, I’d like to begin with the backstory of ML Bio Solutions. We’ve been tracking the growing the ability of patient advocates and rare disease families to catalyze drug discovery and development, and ML Bio is an example of that. Can you explain how ML Bio came to be?

Doug Sproule: Oh, absolutely. It’s really a fantastic story of how parents and families and patients can turn what would otherwise be a tragedy into something not just positive, but really transformative for a patient community. And ML Bio was founded in 2001 by the McColl and Lockwood families. They had an affected child with this disease, specifically called limb-girdle muscular dystrophy type 2i, and they encountered a world where there was limited understanding of the disease, limited understanding of what caused the disease, and there was no prospect of any therapies that would actually treat the disease. And so, they pulled together significant resources, and then just threw it at trying to do some research, but created a laboratory with a specific mission to develop therapeutic strategies and potential therapies to treat this disease. And from that [came] a product we call BBBP-418—it’s also called ribitol—emerged. And ML Bio Solutions was founded to develop this therapy that emerged from the research that was sponsored by the McColl Lockwood Laboratory. And this is a tremendous example of how family can take their tragedy and move a program and turn that into something that can lead to potentially something that could be really instrumental for their family member, but also for thousands of other people affected by this disease in the United States and elsewhere.

Daniel Levine: I just want to clarify one point you said: ML Bio was founded in 2001. You were talking about the research labs?

Doug Sproule: The lab was founded. The McColl Lockwood Lab was formed [in 2001], and ML Bio was founded in 2018 following development in and research that emerged from that organization.

Daniel Levine: In 2019, Bridgebio acquired ML Bio. Bridgebio sought to create an efficient business model that seeks to take a portfolio strategy to mitigate the risk of drug development. It often forms companies around single assets or a group of focused assets. What does being part of Bridgebio mean to ML Bio Solutions? Is there much interaction between ML Bio and Bridgebio? Do they act as investors or do they play more of a hands-on role in the drug development process?

Doug Sproule: Yeah, it’s, it’s been a really remarkable journey as a partner and affiliate of Bridgebio. Bridgebio, as you mentioned, acquired ML Bio Solutions in 2019. That was a decision that was taken to take advantage of significant resources that Bridgebio can bring to bear. And it’s not really financial. There’s money that can be raised from other sources. What they bring is a cross-functional expertise and a passion. Bridge is an organization committed to developing therapies for rare genetic diseases, which limb-girdle muscular dystrophy type 2i is just one. By being an affiliate of Bridge, it gives me access to resources across the organization. One of the biggest challenges when you’re a small company like ML Bio was, with just a handful of employees, is that you’re dependent on the expertise and the feedback that you can get from this very narrow circle of people. And there’s an echo chamber risk and the lack of resources that that brings to bear. Bridge has the availability to leverage assets and resources and expertise, and people who have specific skills across the organization is tremendously helpful in really accelerating our productivity and how quickly we can move this program forward.

Daniel Levine: And the case of ML Bio, is there a good example of how you were able to leverage that?

Doug Sproule: Yeah, absolutely. So, the most primary example is our chief scientific officer who is a woman named Uma Sinha, who is an extremely talented, knowledgeable expert in early stage development, IND execution. This is a woman we could not possibly have afforded to hire to play that role in our company, but we’re able to leverage her presence and use part of her effort. She spends a lot of time working for several other programs. And on the side, she provides critical instrumental work for us as well.

Daniel Levine: Prior to joining ML Bio, you were vice president and therapeutic area head for spinal muscular atrophy for AveXis. This was one of the most closely watched programs at the time, on the cutting edge of rare disease therapies. The company developed the gene therapy Zolgensma. What attracted you to ML Bio?

Doug Sproule: From my perspective, I actually answer that a little bit differently. I take a kind of step back and I’ve had the immense privilege of being able to be involved now in multiple programs, changing the field that I first came into. I’m a pediatric neuromuscular specialist by training, and I was in practice at Columbia University and in New York City. And pediatric neuromuscular medicine is an amazing field. You’re really doing God’s work helping patients and families with devastating neuromuscular diseases manage their diseases, live as normal lives as possible. But the field that I encounter is also an extremely challenging one. I mean, it’s absolutely crushing to diagnose a child with a devastating life altering, life-limiting disease, have the parents turn to you and say, okay, well what are the treatments, what are the treatment options for my child? And in the end saying, yeah, there’s none, and there’s none on the horizon, and we don’t even have a prospect of getting to a therapy. And so, it’s been an immense privilege for me to be able to change that. For my time at AveXis working with a transformative gene therapy product in spinal muscular atrophy, ML Bio has much the same aspirations. Limb-girdle muscular dystrophy type 2i is an untreated untreatable disease that affects thousands of patients and leads to chronic disability, wheelchair dependence in many patients, the need for ventilatory support and ventilators, heart problems, and really is a life altering and life affecting disease. And there is no therapy. And so what attracted me to joining ML Bio was the opportunity to play a ground role in changing that for thousands of patients—and what an immense privilege.

Daniel Levine: Let’s talk a bit more about limb-girdle muscular dystrophy. My understanding is this is not a single disease, but several related diseases with different underlying genetic causes. You’re focused on type 2i. What is that and how does that differ from other forms of limb-girdle muscular dystrophy?

Doug Sproule: Yeah, it really takes a bit of a history lesson. So, one of the things that we forget in the modern era is that molecular diagnoses where you could take a blood test and get a genetic result is not something that we had 50 years ago. It’s not something we even really had 10 years ago. When I when I joined industry in 2013, diagnosing patients with specific forms of limb-girdle muscular dystrophy was practically extremely expensive and very limited. Patients historically were described as having limb-girdle muscular dystrophy based on their symptoms. So, patients would have weakness in their shoulder muscles, in their leg muscles, in their girdle muscles, and thorax. And so they’d have this really kind of proximal big muscle weakness that would lead them to have problems with getting up from a chair, walking, lifting up their arms. Ultimately, it would get worse and worse and affect breathing and their diaphragm and their heart muscles as well. Because we had no ability to really differentiate these diseases, they all kind of looked the same. They were called limb-girdle muscular dystrophy. And then only later when we started to identify the specific underlying causes, did we label individual subtypes. So, limb-girdle muscular dystrophy type 2i is a specific genetic disease that’s caused by the mutation of an enzyme called FKRP, and it causes one of dozens of different forms of limb-girdle muscular dystrophy.

Daniel Levine: How does that complicate the drug developer’s role in terms of going after a single form of limb-girdle? Or do you go after a very specific form?

Doug Sproule: It creates a lot of complexities that affect the development process in different ways. I think the most profound one is just the recognition and identification of patients. So, as I mentioned, until really about 10 years ago, there wasn’t any really straightforward way to identify what type of disease a a patient had. When I was in practice, many of my patients, most of them in fact, were described as having limb-girdle muscular dystrophy, or not otherwise specified. And there’s thousands and thousands of patients who have similarly been diagnosed as having limb-girdle muscular dystrophy without having any real further distinction. And frankly, back in the day, it didn’t make a difference. There were no therapies for any of these diseases. It was expensive, it was limited. What was the point in going down this rabbit hole to find out whatever the specific subtype was. That all changed in 2014. There was a partnership between a foundation called the Jain Foundation, another great example of how patient advocacy organizations can really drive transformations in a field. And they partnered with Genzyme in something called the Lantern Project, and this was basically an effort to leverage the rapid advances in molecular genetics to create panel testing that was funded by industry but run independently through private philanthropy to provide access for genetic testing for patients with limb-girdle muscular dystrophy. And so instead of having A patients on a research basis test for individual types, you’re able to get a free blood test that would diagnose potentially 20 or 30 different forms of limb-girdle muscular dystrophy through one test. And this is really transformed the field, we’ve gone from most patients not really diagnosed to one where now in the modern era in the United States and most other western countries, you will get a diagnosis of your specific form of limb-girdle muscular dystrophy. And that’s really a critical development because it allows you to identify patients, patients to identify the potential research options that they might want to be involved with. And it’s really a critical advance in allowing development of effective therapies.

Daniel Levine: How predictable a progression is there for a patient with limb-girdle? And how do the different types vary in intensity or heterogeneity?

Doug Sproule: Yeah, that’s a really complicated question. Speaking about it broadly there’s a lot of similarity between the different forms of limb-girdle muscular dystrophy, but each of them has vastly different features as far as the rate of progression, the age onset, some of the other sequelae, whether heart problems are really predominant or whether they’re not such a big deal. For limb-girdle muscular dystrophy type 2i, most patients will develop symptoms during childhood, depending on the severity of their underlying mutation. Some will present early in childhood, like age five, others will present during their teen years and there’s a bit of a heterogeneity to the disease, even if you’re just talking about LGMD2i. But patients will typically present, and they’ll have this, what from a researcher’s perspective is slow, but from a patient’s perspective is inexorable progression of disease. They’ll get consistently and consistently worse and worse and worse and worse over time. Children who develop symptoms during the first decade of life are typically wheelchair dependent. They lose the ability to walk by the time they’re 20. For patients who develop symptoms later, like during their teen years, about half of those patients will wind up wheelchair dependent by midlife. And so this is a disease that has profound impact on a patient’s life.

Daniel Levine: And are there treatment options that exist today?

Doug Sproule: So, right now the only treatments that are available for patients with limb-girdle muscular dystrophy type 2i are rehabilitative care, which is critical. Physical therapy—being active, swim therapy—these are the things that keep patients limber and keep patients as functional as possible. Some patients will require scoliosis surgery to help maintain body positioning. But practically speaking, it’s very limited what you’re able to do for these patients. There are no effective disease modifying treatment for patients with limb-girdle muscular dystrophy type 2i.

Daniel Levine: And are steroids used to treat the condition?

Doug Sproule: steroids have been used historically to treat a different form of muscular dystrophy called Duchenne muscular dystrophy. So, one of the things that’s always been raised is, “well, if it seems to work in that disease, would it work in other forms of muscular dystrophy?” And unfortunately, what evidence there is suggests that it doesn’t help for patients with limb-girdle muscular dystrophy. And so it’s generally not used for the most part.

Daniel Levine: And how are patients generally diagnosed with the condition?

Doug Sproule: So now, in the modern era what typically happens is a patient would present, and obviously everybody’s story is different, but typically would present to a pediatrician and ultimately would get referred to a neurologist and then onward to a neuromuscular specialist. A neuromuscular specialist would typically recognize the symptoms of proximal weakness, trouble rising from the floor. The patient may have some blood tests, which show an elevated creatine kinase level, which is a muscle enzyme that is released when the muscle cells break down. And based on those symptoms, would perform a molecular blood test that would diagnose the specific form of limb-girdle muscular dystrophy. And in the case of patients with LGMD2i, I would diagnose the specific underlying mutation that was causative for the disease.

Daniel Levine: ML Bio is developing BBP-418. This is a pro-drug. Can you explain what it is and how it works?

Doug Sproule: Yeah. So, you know, that’s where the story gets a little bit complicated. So, limb-girdle muscular dystrophy type 2i is caused by a mutation of an enzyme called FKRP. And FKRP is involved in this process called glycosylation of another protein called Alpha dystroglycan. So Alpha dystroglycan is kind of the critical linchpin protein on our muscle cells. I would describe it as kind of a shock absorber for the muscle cells and when it doesn’t work, the muscle cells are subject to chronic injury and ultimately death and replacement and loss, which ultimately results in muscular dystrophy. And so, FKRP is involved in attaching a sugar molecule to a chain of sugars called a glycan chain. And this glycan chain is a critical component of Alpha dystroglycan. So, if FKRP doesn’t attach that sugar, the glycan chain doesn’t form correctly, alpha dystroglycan doesn’t then work correctly, and then everything falls apart. And so, FKRP uses a sugar called CDP-ribitol, and it attaches a ribitol phosphate molecule to that glycan chain. And so, what we do is we provide in the form of BBP-418, a synthesized version of ribitol, which is produced naturally by the body, but we provide lots and lots and lots of it. It’s converted into lots and lots and lots of CDP-ribitol, and it’s hoped that by giving lots and lots of that substrate, the substance that the enzyme uses, that you can drive forward more of that fully formed, fully functional glycan chain formation. So, I would kind of liken it to a fire. This isn’t really burning and you pour lots and lots and lots of fuel on it to help it work a little bit better. And so, it’s a simple, elegant solution to a really complicated problem.

Daniel Levine: Is the expectation that this would slow progression, halt progression, or is there any potential it would reverse the disease?

Doug Sproule: That is a really complicated question. So, what we’ve seen in our early trials is that there’s some evidence that patients can actually experience some degree of recovery. We’re seeing some actual improvement in the open label phase 2 study of the disease, which gives people the hope that not only could you potentially help progression if you were able to treat early enough, but that you could allow the body to heal and recover and actually improve. That said, that’s not necessarily the goal. When we talk to patients who are affected by this disease, what they’re very emphatic about is that they don’t like where they’re at now. They mourn what they’ve lost as far as their abilities, but they’re terrified of what they see in the future as far as what they’ll lose next. And so, as we’re approaching our development, our goal is to slow, particularly halt, progression of the disease and show that our product, if it allows patients to get better, that’ll be awesome. And you know, I think that’s our personal expectation. But just slowing the disease down would be a major advance for patients affected by this disease for which there’s no treatment and no prospect of treatment.

Daniel Levine: The company announced positive results from a phase 2 trial last year. What’s known about the safety and efficacy of it?

Doug Sproule: Yeah, as I was alluding to, we’ve conducted a phase 2 trial. It’s an open label study and it’s ongoing. And we’re extremely excited about the results that we’re seeing from that study. So, what we’ve seen from a safety perspective is that this drug has been remarkably well tolerated. The only side effects that we’re seeing are some stomach upset some patients have that’s generally transient, but it’s been very well tolerated, which we hope will be consistent in our bigger studies, reflective of the fact that this is a synthesized version of something that our body already produces. From an efficacy standpoint, we’re really excited about the early data. We have a bioassay that measures that glycosylation of alpha dystroglycan. And we’re seeing that muscle cells are showing a much bigger really marked improvement in the amount of alpha dystroglycan that’s fully glycosylated after treatment with BBP-418, which suggests that the drug is doing something at least on the level of the cell creatine kinase, which I mentioned is a marker of muscle cell breakdown. And we’re seeing that the creatine kinase levels are going way down after treatment with this drug as well. And we’re also starting to see some signs from the clinical side as well. We’re seeing an improvement in a clinical function test called the North Star Assessment which is a clinical function assessment that’s used in patients with limb-girdle muscular dystrophy. And we’re also seeing some signs, the patients are starting to actually walk a little faster when measured using some of our ambulatory assessments as well.

Daniel Levine: What’s the development plan going forward?

Doug Sproule: So, we’re excited to be advancing in phase 3 later this year. Our hope is that we’ll be getting into the clinic in the next several months. The timeline is obviously subject to so much variability that it would be remiss of me to speculate on the specific, but we’re moving very quickly and as fast as we can into phase 3, and we’re really excited to be advancing this program forward.

Daniel Levine: And how big a study do you expect that to be? What are you going to be using for as endpoints?

Doug Sproule: So, we’re going to be looking at a number of clinical endpoints. This is a disease that affects motor function—our ability to roll, to sit stand, to walk—we’re going to measure ambulatory function. We’re going to measure a disease that’s marked by impairment of breathing. So, we’re measuring how well patients breathe. We’re going to be looking at measures of the heart. We’re going to be looking at measures of how the upper limb works, so how well you can use your arms in accomplishing tasks. So, we’re going to be assessing a whole host of different endpoints because this disease progresses insidiously and relatively gradually over time from the standpoint of a trial where you’d like to do things in a year or six months, or as short as you can. This is going to be a relatively long study or a large study. We expect to enroll somewhere between 80 and 100 patients and this is going to be conducted over a longer term as well.

Daniel Levine: And what happens to ML Bio with the success or failure of BBP-418? Will BridgeBio commercialize it on its own? Do you find a commercial partner, or is there a pipeline behind this?

Doug Sproule: Yeah, it’s a fascinating question and the great part from my perspective is it’s outside my lane to even answer it. But I would say that from my perspective, the goal that I’ve always had in being part of ML Bio is to develop this product to address a critical unmet need in the neuromuscular community. And regardless of how we get there with regard to the commercialization strategy, whether BridgeBio invests in commercializing it itself or finds a partner, from the patient perspective, the critical question is, “Are we going to be able to be successful in developing this product to meet the regulatory obligations that we have to demonstrate its safety and efficacy and get it made available to patients?” I think from my perspective, that’s where my focus is. And I know that’s where my colleagues’ focus is as well. And you know, how we best operationalize the commercialization will be a great question for another day.

Daniel Levine: Doug Sproule, chief medical officer of ML Bio Solutions. Doug, thanks so much for your time today.

Doug Sproule: Absolutely. It’s a real pleasure to have the opportunity to speak with you today. And for additional questions people might have, I’d encourage people to go to our website, mlbiosolutions.com and certainly send us a note.

This transcript has been edited for clarity and readability.