The vice president of clinical development at Biohaven provided insight on a new phase 3 study assessing a muscle-targeted agent as an adjunct therapy to currently approved spinal muscular atrophy medications.
Spinal muscular atrophy (SMA), a fatal neuromuscular disorder caused by a mutation in the survival motor neuron gene 1 (SMN1), has a spectrum or severities that range from early onset with respiratory failure during the first months of life to a mild adult-onset type with slow rate of progression. After decades of no approved therapies, the FDA cleared Biogen’s SMN-enhancing therapy nusinersen (Spinraza) in 2016 as the first to treat the disease. Since then, the FDA has approved 2 other therapies—Genentech’s risdiplam (Evrysdi) and Novartis’ gene therapy onasemnogene abeparvovec (Zolgensma).
A new agent, Biohaven’s taldefgropeb alfa, may be next in line to join the market. In early June, the company announced the first patient had been dosed in a new phase 3 study—called RESILIENT (NCT05337553)—that will evaluate the therapeutic in a cohort of 180 patients with SMA, regardless of ambulatory status or SMA type. Previously known as BMS-986089, taldefgropeb alfa was originally developed by Bristol Myers Squibb and studied in other neuromuscular conditions such as Duchenne muscular dystrophy.
To learn more about this new trial, including the reasons behind the hype of taldefgropeb alfa, NeurologyLive® sat down with Linsdey Lee Lair, MD, VP, Clinical Development, Biohaven. As part of a new edition of NeuroVoices, Lair discussed the promising mechanism of action of the agent, how it is used with other currently approved medications, and why its established safety and tolerability profile give it a leg up in its clinical journey.
Lindsey Lee Lair, MD: Spinal muscular atrophy or SMA is a neuromuscular, neurodegenerative disorder that affects the skeletal muscles and often leads to devastating, progressive weakness and functional impairments. The current disease modifying therapies aim to help patients achieve milestones they otherwise would not have and improve survivability. Despite this, these therapies don’t target the muscles themselves, so patients are often left with residual weakness and functional impairments. Therapies that target the muscle are needed. Given this large unmet need, we at Biohaven are excited about our phase 3 RESELIENT trial with taldefgropeb alfa. It’s a novel antimyostatin that targets the muscle, and we’re investigating it as an adjunctive therapy on top of the current standard of care to assess the potential to further increase skeletal muscle function and capabilities of children and adults with spinal muscular atrophy.
Myostatin is a negative regulator of skeletal growthand blocking myostatin has been shown to lead to skeletal muscle enlargement. Taldefgropeb alfa is an antimyostatin that targets the muscle and has a dual activity, so it suppresses myostatin levels but also blocks receptor signaling. It already has an established safety and tolerability profile. We’re proud to also be taking a patient-centric approach to our trial. When we speak with our investigators here, they liked the fact that we’re looking to study in a broad range of patients with SMA. We’re not limiting it based on background therapy or ambulatory status or even SMA type.
The current disease-modifying therapies are helping patients achieve milestones they haven’t achieved before, and we do know that there is use of combination therapies as the field progresses. All the current disease-modifying therapies aim to upregulate SMN protein, and don’t target the muscle themselves. These therapies are needed. Taldefgropeb alfa is an antimyostatin that aims to target the muscle with a dual activity.
The prior studies were important to help us understand that we could dose the drug subcutaneously, weekly, in the clinic or at home, and still achieve suppressed myostatin levels. It also helped establish a safety and tolerability profile, which is really important as you move into phase 3 settings for SMA. Once again, we’re quite proud that we’re evaluating taldefgropeb alfa as an adjunctive therapy in a broad patient population, and not limiting or restricting based on ambulatory status, background therapy, SMA type or SMN copy number.
We’re [also] excited about the fact that we have started enrolling. With these clinical trials, the length of time depends on the enrollment. Our primary end point is at 48 weeks, and we’re looking forward to collecting that data in the future.
We’re proud in the field of how far we’ve come on the disease-modifying therapies, the widespread newborn screening, and the combinations of therapies. We still know there’s an unmet need in this community and these children and adults living with SMA are still experiencing weakness and functional impairments. That is why we’re investigating taldefgropeb alfa to further improve the functional capabilities of these patients. I wanted to thank the entire SMA community, the children and adults living with SMA, the study participants, parents, and other family members, caregivers, advocates, and health care providers.
Transcript edited for clarity. Click here for more NeuroVoices.