RARE Daily

Stimulating the Growth of Muscle Mass in People with Neuromuscular Diseases

October 26, 2023

While there have been significant advances in the treatment of the rare, neuromuscular condition spinal muscular atrophy, existing therapies that slow or halt progression of it don’t regenerate muscle that has been lost. Biohaven is developing a therapy designed to inhibit myostatin, a protein that regulates the growth of skeletal muscle growth. We spoke to Lindsey Lee Lair, Biohaven’s vice president of clinical development, about SMA, the progress we’ve seen in treating the condition, and the company’s efforts to develop a therapy to stimulate the growth of muscle mass and strength in people with the disease.

Daniel Levine: Lindsay, thanks for joining us.

Lindsey Lee Lair: Thank you so much for having me, Danny. I really appreciate the opportunity to be here today.

Daniel Levine: We’re going to talk about spinal muscular atrophy, Biohaven, and its efforts to develop a muscle targeting therapy for people with the condition. Let’s begin with SMA. For listeners not familiar with it, what is it?

Lindsey Lee Lair: Spinal muscular atrophy, or SMA, is a rare genetic neurodegenerative disorder. It affects the nerve cells in the spinal cord and brainstem, and it results from a mutation in a specific gene. It’s called the survival motor neuron 1 gene or the SMN1 gene. This leads to insufficient production of survival motor neuron protein or SMN protein, which is essential for normal motor neuron function. Now there’s a second gene called the SMN2 gene that produces very low levels of SMN protein, but it’s just not enough to compensate and produce the full amount. So this leads to motor neuron death and the atrophy or shrinkage of skeletal muscle or the voluntary muscles in the body. The more copies of SMN2 that somebody has, the more protein they make and the milder their disease, but it still leads to progressive muscle weakness, difficulty speaking, walking, breathing, swallowing. So it’s just a devastating condition. It’s typically diagnosed in young children and it’s often fatal and always life altering. SMA does occur in about one in 10,000 births and about one in 50 people are genetic carriers.

Daniel Levine: How does the condition manifest itself and progress?

Lindsey Lee Lair: So, spinal muscular atrophy, or SMA, affects the skeletal muscles, the voluntary muscles in the body, so it affects functioning across many parts of the body. There is progressive muscle weakness, spasticity, contractures, which are basically joints frozen in place, so immovable. There can be bone fractures, hip dislocations, scoliosis, which is the curvature of the spine. There can be paralysis and in the most severe cases, tragically it can result in death. It can affect infants, children, or adults of any race or gender. And the natural history of SMA is really variable. So natural history, meaning those who are untreated, this is before the disease modifying therapies were available. And historically there were different types of SMA, again, based on those SMN2 copy numbers and the functional capabilities and the age of onset, the most common type is type 1, which is the most severe, and its onset is in infancy. And those may never sit independently and may tragically die before their second birthday. Those living with SMA-2 may be able to sit but not stand. Those with SMA-3 may stand or may walk, but with difficulty and have decreased muscle tone, decreased muscle bulk. There’s a milder form that presents in adulthood, which is SMA type 4, but many of those living with SMA are wheelchair reliant. SMA can affect respiratory muscles, so problems with breathing, problems with sleep, increased severity of severe chest infections, respiratory distress, and many times there’s a need for respiratory support or help with breathing. SMA can also affect other organ systems like the gastrointestinal system or the GI system, can result in swallowing difficulties, often known as dysphasia. And there could be need for nutritional support or even just in general feeding support. So, with the innovation of new therapies, the historical classification is not quite as relevant because thankfully these people living with SMA who are treated are achieving milestones they would not have otherwise achieved. So, the field is moving away from the classical SMA type that we always hear about and focusing more on the function of the people living with SMA and what the capabilities are that they can achieve.

Daniel Levine: You mentioned the new therapies for SMA. We have seen enormous innovation in this area. We’ve had the ASO Spinraza, the gene therapy Zolgensma, and the small molecule therapy Evrysdi all come to market. I think people may wonder why a company would pursue a treatment for SMA given the range of therapeutic options today. What are the limits of existing therapies and what’s the problem Biohaven is seeking to address?

Lindsey Lee Lair: That’s a great question. To be clear, there is no cure for spinal muscular atrophy. So, the current therapies really have helped people living with SMA achieve milestones they would not otherwise achieve. But they’re all aimed at increasing SMN protein production. They improve the motor neuron functioning, but they don’t target the muscles themselves. So there’s still a significant unmet need in this area. There’s residual weakness, residual functional impairments, difficulty walking, and difficulty still achieving the activities of daily living, the ADLs. Those are the fundamental skills required to independently care for oneself such as eating, bathing, and mobility. So the help of a parent or other caregiver is often needed. Treatments that are aimed at increasing muscle strength and function would certainly be welcomed by the SMA patient community. Even modest gain in function, improving feeding capabilities using a cell phone to communicate, these are things that can significantly improve someone’s quality of life.

Daniel Levine: In other words, if the existing therapies are able to halt the disease, that does nothing to reverse its progression.

Lindsey Lee Lair: Well, right. It supports the motor neuron functioning, but there still can be atrophy of the muscles and still significant residual weakness, functional impairments, the muscle tissue in SMA largely remains intact. So that really allows for an opportunity to target the muscle with the potential muscle targeting therapy, which is a really exciting thing.

Daniel Levine: I want to ask you about Biohaven’s therapy, but before we do that, I thought it might be useful to have you explain what myostatin is and the role it plays.

Lindsey Lee Lair: So myostatin is a natural protein. It’s expressed by skeletal muscle and it’s a negative regulator of muscle growth. So it’s actually really important for healthy muscle development. Blocking myostatin leads to enlargement of skeletal muscles, and this has been validated by human genetics and supported by nonclinical data across numerous species. So, if you think of it, myostatin as a brake that slows down this process. If we could take our foot off the brake with a therapy that could allow muscles to enlarge, that really opens up a potential therapeutic possibility.

Daniel Levine: What happens, if anything, to myostatin in people with SMA?

Lindsey Lee Lair: So again, the healthy muscle development is controlled in part by myostatin, which is that naturally occurring protein. It’s a negative regulator of skeletal muscle growth and in neuromuscular diseases and in SMA in particular, myostatin can limit the muscle growth that’s needed to achieve various developmental and functional milestones. So inhibiting or blocking that myostatin is really opening the potential to enhance muscle mass and strength in these people living with SMA.

Daniel Levine: Biohaven is developing an experimental therapy that is a myostatin inhibitor. What exactly does it do?

Lindsey Lee Lair: Taldefgrobep alpha, also known as taldefgrobep, is an investigational muscle targeted myostatin inhibitor. It blocks a receptor complex formation that actually reduces downstream signaling in order to inhibit myostatin. So again, the current available therapies really focus on SMN protein upregulation and rescue neuronal death, but they don’t target the muscle. And as we were talking about before, in SMA patients, the muscle tissue largely remains intact. And in fact, in SMA mouse models, combination therapy with an SMN up-regulating therapy in addition to a myostatin inhibitor has been shown to improve muscle function. So, in the clinic, we’re looking to study a combination therapy with taldefgrobep on top of an SMN up regulator, or SMN up regulators, and the potential to improve motor function and clinical measures.

Daniel Levine: There’s been a fair bit of interest within the SMA community to explore regenerative therapies. What’s the potential here for a regenerative therapy that can reverse the damage caused by the disease and how important is that to the patient community?

Lindsey Lee Lair: Yeah, so because the current therapies are really focusing on the motor neuron, strategies that target the muscle are really needed, again, the muscle tissue in SMA largely remains intact. So targeting that really can provide an opportunity on top of the standard of care disease modifying therapies to really fill that significant unmet need that remains to address potential residual function, functional impairments, and even helping people complete ADLs or the activities of daily living. So even modest gains, again, could really help improve quality of life and be really welcomed by the SMA patient community.

Daniel Levine: Your experimental therapy targets not only muscle, but also adipose tissue. What is the significance of that?

Lindsey Lee Lair: Yes, that’s right. So, taldefgrobep is an investigational protein that has the potential to induce not only physical, but also metabolic changes, which is highly relevant to those that live with overweight and obesity. Obesity is a disease of excess and/or abnormal deposits of adipose tissue, also called body fat. And obesity is a global public health crisis. By 2030, which if you think about it is not that far off, about a billion people will live with obesity. About half of the adult population and about a quarter of the adolescent population in the United States will be affected. And the current anti-obesity therapies are really trying to target weight loss by the reduction of both fat mass and lean muscle mass. Taldefgrobep has a unique mechanism of action and provides a potential novel approach to reducing abnormal and excess body fat, which is the primary pathology of obesity.

Daniel Levine: So, is Bio Haven looking at this as a potential therapy for obesity as well?

Lindsey Lee Lair: We are looking at the potential of taldefgrobep and studying that in those with overweight and obesity.

Daniel Levine: What’s known about taldefgrobep from studies that have been done to date?

Lindsey Lee Lair: So, taldefgrobep has been studied in a number of nonclinical as well as clinical studies. Those in healthy volunteers, adults, and two studies in boys with Duchenne muscular dystrophy or DMD, which is another neuromuscular disorder. In those studies, 359 participants have received taldefgrobep, 179 healthy adults received taldefgrobep, and 180 boys with DMD. And from those studies we were able to really understand alot about taldefgrobep, the ability to administer as a subcutaneous injection, which is an injection just underneath the skin, and that it can be given in clinic or at home. And we saw a dose dependent suppression of free serum myostatin and repeated dosing of up to 35 or 50 milligrams based on the body weight was generally safe and well tolerated. And this is really important because all of these findings helped us really understand the safety and tolerability profile and the dosage and administration, which allowed us to bring taldefgrobep into our phase 3 study in spinal muscular atrophy.

Daniel Levine: In September, the company completed enrollment in a pivotal phase 3 study. How big a trial is this and what are the endpoints you’re using?

Lindsey Lee Lair: So, we are really excited to complete enrollment in our RESILIENT trial, which is a pivotal phase 3 clinical trial in SMA. We so named the trial because of the resilience, the perseverance, and never give up attitude of the patients and the community of SMA, and about 180 participants are planned to be randomized in nine countries, and we’re studying the efficacy and safety of taldefgrobep as an adjunctive or a combination therapy versus placebo for the potential to improve muscle volume and function in children and young adults living with SMA. It’s a randomized double-blind placebo controlled phase 3 study, and there’s a two to one randomization scheme, meaning that there’s a 66 percent chance that someone in the trial will receive taldefgrobep in the double-blind treatment phase. We talked a lot about the treatment side that are now available, and there’s also newborn screening, which has the potential to identify and diagnose those with SMA very early in life. And this is becoming more and more widespread, which is really exciting because the early diagnosis enables an earlier treatment and we’re even seeing combinations of therapies in the field. So, the field has just evolved tremendously over the last so many years. And as such, those living with SMA are achieving milestones they wouldn’t otherwise achieve. And there’s really been this shift to focus on the functional status of the person with SMA as opposed to the classical SMA types. So, given the high unmet need in this area, the changing treatment paradigms, we at Biohaven want to take a really patient-centric approach in this trial and we’re really proud of that. We enrolled a broad patient population, so RESILIENT is not restricted or limited by ambulatory status or background therapy, SMN2 copy number, or classification. We’ve enrolled children and adults four through 21 years of age with a confirmed genetic diagnosis of SMA and we enrolled ambulant and non-ambulant participants. So those are people that can walk and also that can’t walk, but who are able to sit independently so long as they were on a stable regimen of their SMN up-regulating therapy and anticipated to remain on that therapy throughout this study. So that would include nusinersen, risdiplam and/or onasemnogene abeparvovec-xioi (Zolgensma), and even allowed for combinations of those therapies so long as the regimen was stable. And again, we’re trying to take a very patient-centric approach with this trial. And taldefgrobep or placebo is given subcutaneously once weekly, again that’s just under the skin. Doses can be rotated in the arm, the thigh, the abdomen, and can be given during the clinic visits or at home after the baseline visit. The visit to the clinic are about every 12 weeks and taldefgrobep is given in a weight-based fashion, meaning there’s a dose of 35 milligrams or 50 milligrams based on the weight. There’s an optional open-label extension after the double blind treatment phase. That’s 48 weeks. In the optional open-label extension, all participants will receive taldefgrobep for 48 weeks. And we’re looking at a primary endpoint to evaluate efficacy, looked at by a scale to measure function. So, our primary endpoint is the change in the 32 item motor function measure, or MFM32, total score between baseline and week 48. And RESILIENT will also assess the safety and tolerability of taldefgrobep alpha.

Daniel Levine: And if all goes well, when might Biohaven be in a position to file for approval?

Lindsey Lee Lair: So, we at Biohaven are really excited to recently just [have] completed our enrollment and we do have a 48 week primary endpoint. It’s a bit too early to discuss the timing of regulatory approval, but we’re really excited about how this study’s moving along so far. And we really wanted to take the opportunity to thank the entire SMA community, the patients, the parents, families, the caregivers, the healthcare providers, the advocates, and the participants who are enrolled in our study and others helping to research potential treatments for SMA—a really big thank you.

Daniel Levine: You alluded to DMD earlier. There are certainly many other neuromuscular conditions where treatments are emerging. What’s the potential to apply the same therapeutic strategy to these other conditions and what’s Biohaven doing, if anything, to address that?

Lindsey Lee Lair: Biohaven is committed to scientific innovation in the treatment of disease and our track record bears this out. In addition to SMA, we have studied in other diseases with a high unmet need, for instance, like spinal cerebellar ataxia, among other debilitating diseases. And we will continue to follow the science as we investigate new potential treatments for patients.

Daniel Levine: Is the expectation though that this drug could be applied to other neuromuscular conditions and potentially have the same benefit?

Lindsey Lee Lair: Well, we’re absolutely looking to see the results of our RESILIENT trial and we will continue to follow the science as we learn more about our investigational compound to potentially look into treatments for patients.

Daniel Levine: Lindsay Lee Lair, Biohaven vice president of clinical development and lead for the company’s SMA program. Lindsay, thanks so much for your time today.

Lindsey Lee Lair: Thank you so much Danny, really for this opportunity to be in Rarecast and the opportunity to discuss SMA and Biohaven’s RESILIENT phase 3 trial in SMA. Really appreciate it. Thank you so much.

This transcript has been edited for clarity and readability.


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