Adding New Mechanistic Agents to SMA Treatment: the Phase 3 RESILIENT Study


Lindsey Lee Lair, MD, a neurologist and vice president of clinical development at Biohaven Pharmaceuticals, provided insight on an ongoing pivotal trial assessing the impacts of taldefgrobep alfa, a myostatin inhibitor, in patients with SMA.

Lindsey Lee Lair, MD, a neurologist and vice president of clinical development at Biohaven Pharmaceuticals

Lindsey Lee Lair, MD

Spinal muscular atrophy (SMA) is a lower motor neuron disease with autosomal recessive inheritance that results in progressive proximal muscle weakness and skeletal muscle atrophy. The incidence of SMA is approximately 1 in 10,000 to 20,000 live births, and the carrier frequency is 1/40 to 1/70 in the general population. SMA, derived into 5 subtypes, is believed to be the leading genetic cause of infant mortality.

In 2016, nusinersen (Spinraza; Biogen) was the first drug approved for the treatment of SMA in the United States. A few years later, 2 other drugs, onasemnogene abeparvovec (Zolgensma; Novartis) and risdiplam (Evrysdi; Genentech), were subsequently approved, giving patients a gene therapy option and another survivor motor neuron (SMN)-enhancing therapy. While these therapies are not curative by any means, they signaled a significant change in the field, giving patients with SMA hope for the future of their condition.

There is promise surrounding taldefgrobep alfa (Biohaven Pharmaceuticals), a new agent in development for SMA. At the 2024 American Academy of Neurology (AAN) Annual Meeting, held April 13-18, in Denver, Colorado, researchers presented an outline of the phase 3 RESILIENT study (NCT05337553), a large-scale, fully enrolled, placebo-controlled trial assessing the effects of taldefgrobep alfa in various forms of the disease.

Lindsey Lee Lair, MD, a neurologist and vice president of clinical development at Biohaven Pharmaceuticals, sat down with NeurologyLive® during the meeting to discuss the study the excitement behind taldefgrobep alfa and the phase 3 RESILIENT study. She spoke specifically about the mechanism of action of the therapy, a fully human anti-myostatin adnectin recombinant protein, and how it may be used in the treatment landscape of SMA. Furthermore, she gave context on how it differs from other previously approved therapies and when the clinical community can expect to hear data readouts from RESILIENT.

What does your presentation at AAN 2024 entail?

Biohaven is really excited about our poster presentation on the phase 3 RESILIENT study that we were able to present at the 2024 American Academy of Neurology Annual Meeting. It’s a global study of our novel myostatin inhibitor taldefgrobep alfa or BHV-2000. The therapy is used in combination with background standard of care therapies to potentially further increase muscle function in children and adults living with spinal muscular atrophy or SMA. RESILIENT is looking to test the efficacy and safety of taldefgrobep alfa in SMA.

SMA is a rare, neurodegenerative neuromuscular disorder caused by an aberrancy of the survival motor neuron 1 or SMN1 gene. It results in motor neuron loss and progressive deterioration of skeletal muscle, which causes devastating weakness. [These patients face] problems with things like breathing, swallowing, and walking. The SMA upregulators really help improve survival and functional milestone achievement, but they focus on increasing SMN protein. They don't target the muscle directly themselves. taldefgrobep alfa, our novel myostatin inhibitor, directly targets the muscle. That’s what we're studying in our phase 3 trial in combination with standard care to hopefully increase muscle function in SMA.

How does this agent differ than previously approved therapies for SMA?

SMN upregulator therapies all increase that SMN protein, rescues the motor neuron, and therefore improves survival and function. But there's still a huge unmet need because they don't directly target the muscles, so patients are still experiencing significant functional impairments, quality of life impairments. A treatment that targets the muscle, like taldefgrobep alfa, or novel myostatin inhibitor, would be used in combination with those background standard of care therapies to hopefully further improve muscle function and SMA.

What is the demographic makeup of the patient population in RESILIENT?

Our study is fully enrolled, it’s ongoing, and we're really excited about that. There is a huge unmet need across the spectrum of SMA, and that's what we had in mind when we were designing our trial. We're proud that we took a very patient-centric approach to enroll a broad population across SMA. RESILIENT doesn't limit based on ambulatory status, or background standard of therapy, the traditional SMA type, or SMN2 copy number. We were able to enroll both ambulant and nonambulant participants 4-21 years of age, regardless of traditional SMA type, as long as they were on a stable regimen of that background SMN upregulator therapy.

Has there been any conversations about interim analyses or completion dates?

We’re fully enrolled with 269 participants across 53 sites in 9 countries. We do plan on having the completion of our double-blind portion of the study, as well as topline results, in the second half of 2024.

Pending the study’s success, could a new drug application be on the horizon?

The study is still ongoing, but we do expect topline results, as mentioned, in the second half of 2024. We would expect to have to taldefgrobep alfa be used in combination with a standard of care therapy, considering that is how we studied it. Hopefully, that's how it could potentially be used, once we know what our data is and we analyze everything.

Is there anything else noteworthy with the drug and its mechanism?

I can talk a little bit about the mechanism of our compounds. I mentioned taldefgrobep alfa is a novel, unique, myostatin inhibitor. Myostatin is actually a naturally secreted protein that is a negative regulator of skeletal muscle growth. Blocking myostatin has actually been shown to lead to enlargement of skeletal muscle. Taldefgrobep works uniquely in suppressing free serum myostatin by inhibiting active myostatin, but also inhibiting the activin receptor type 2b signaling to potentially increase the muscle mass. It has been studied previously in clinical trials and has a well-documented safety and tolerability profile.

It’s given subcutaneously weekly in a weight-based fashion, which can be done in the clinic or at home. We have our trial design in a 2:1 randomization fashion, meaning for every two participants that receive taldefgrobep alfa, one receives placebo, in addition to standard care therapy. That's our double blind phase, which is 48 weeks, and then we have an optional open-label 48-week extension phase where everybody would receive taldefgrobep alfa, and then a period of safety follow up. It’s worth mentioning that our primary endpoint looks at functional abilities, examining change in the total score on the 32-item Motor Function Measure or the MFM 32, over that 48-week period.

To date, what does the safety profile look like for this agent?

The phase 3 RESILIENT study is first time we’re studying this agent in this SMA population. In addition to the efficacy, we’ll also be observing safety, and we'll have a lot more information once we have our unblinded study results. But from our prior clinical trials, taldefgrobep alfa has a really well-established safety and tolerability profile that allowed us to move into the RESILIENT study.

Transcript edited for clarity.

1. Lair L, Qureshi I, Bechtold C, et al. The phase 3 RESILIENT study: taldefgrobep alfa in spinal muscular atrophy. Presented at: 2024 AAN Annual Meeting; April 13-18; Denver, CO. Abstract 003255
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