Efficacy and Safety Evaluation of Taldefgrobep Alfa in Ambulatory and Non-Ambulatory Spinal Muscular Atrophy Patients on Stable Nusinersen/Risdiplam Regimen

The primary objective of this study is to evaluate the **efficacy** of taldefgrobep alfa in participants with Spinal Muscular Atrophy who are already on a stable regimen of nusinersen and/or risdiplam and/or have a history of onasemnogene abeparvovec-xioi. This will be compared to placebo, with efficacy measured by the change in the 32-item Motor Function Measure (MFM-32) total score from baseline to Week 48. This objective is clinically relevant as it aims to determine the potential of taldefgrobep alfa to improve motor function in patients with Spinal Muscular Atrophy, a condition characterized by progressive muscle weakness.

Secondary objectives include:

• Comparing the efficacy of taldefgrobep alfa to placebo using the Revised Upper Limb Module (RULM).
• Comparing the efficacy of taldefgrobep alfa to placebo using the Revised Hammersmith Scale (RHS).
• Assessing the safety and tolerability of taldefgrobep alfa, including changes in lean body mass and bone mineral density on DXA scan at Week 48, Tanner staging for puberty monitoring, new or worsening lab abnormalities, injection acceptability assessments, treatment-related adverse events (AEs), serious AEs, and AEs leading to discontinuation.
• Assessing pharmacokinetic (PK) parameters of taldefgrobep as estimated with population PK modeling.

The clinical trial involves a total of **76 participants** diagnosed with **Spinal Muscular Atrophy** (SMA), confirmed by genetic diagnosis of 5q-autosomal recessive SMA and SMN2 copy number. The study population includes both male and female subjects, encompassing an age range from children to adults. Participants are either ambulant or non-ambulant and are currently on a stable regimen of SMA disease-modifying therapies such as nusinersen, risdiplam, or have a history of onasemnogene abeparvovec-xioi treatment. The trial population was selected based on their current treatment regimen and the expectation that they will continue with the same dosage throughout the study. The study includes a vulnerable population, reflecting the specific health needs and considerations of individuals with SMA. Lifestyle factors such as diet and physical activity are not specified, but the focus remains on the efficacy of taldefgrobep alfa in conjunction with existing SMA treatments.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of **taldefgrobep alfa** in participants with **Spinal Muscular Atrophy** (SMA). The trial will include both ambulatory and non-ambulatory participants who are already on a stable regimen of nusinersen, risdiplam, or have a history of onasemnogene abeparvovec-xioi treatment. The primary objective is to assess the change in the 32-item Motor Function Measure (MFM-32) total score from baseline to Week 48. Secondary endpoints include changes in the Revised Upper Limb Module (RULM) and Hammersmith Functional Motor Scale Expanded (RHS) scores, as well as safety and tolerability assessments.

The trial will span approximately 96 weeks, with participant involvement expected to last until the end of the study. The sequence of study visits includes an initial screening visit to confirm eligibility based on genetic diagnosis and treatment history, followed by regular follow-up visits to monitor efficacy and safety parameters. The end-of-study visit will conclude the participant's involvement, with assessments to evaluate the overall impact of the treatment.

Participants will be randomly assigned to receive either taldefgrobep alfa or a placebo, administered as a solution for injection in pre-filled syringes. The maximum daily dose for taldefgrobep alfa is set at 35 mg or 50 mg, depending on the specific formulation used. Conditions that may lead to early termination from the study include the occurrence of serious adverse events, treatment-related adverse events, or new or worsening laboratory abnormalities. The trial is not categorized as low intervention and is classified as a Phase III study, indicating its advanced stage in the clinical development process.

The clinical trial involves the administration of **Taldefgrobep Alfa**, an experimental medication, which is a **solution for injection in a pre-filled syringe**. The active substance, **taldefgrobep alfa**, is a protein of other origin, developed by Biohaven Pharmaceuticals, Inc. The medication is administered via subcutaneous injection. Two dosing regimens are being evaluated: a maximum daily dose of 35 mg and a maximum daily dose of 50 mg, with a total treatment period of up to 96 weeks. The medication is classified as a biological product and is not a pediatric formulation. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

The study also includes a **placebo** group, which receives a placebo solution for injection in a pre-filled syringe. The placebo is designed to match the experimental medication in appearance and administration route to maintain the double-blind nature of the trial. Participants in the placebo group receive injections at the same frequency as those receiving Taldefgrobep Alfa, ensuring consistency in the administration schedule across all study arms. The placebo serves as a comparator to evaluate the efficacy and safety of Taldefgrobep Alfa in participants with Spinal Muscular Atrophy.

The efficacy of **taldefgrobep alfa** in the clinical trial will be assessed primarily through the change in the 32-item Motor Function Measure (MFM-32) total score from baseline to Week 48. This primary endpoint is designed to evaluate the improvement in motor function in participants with Spinal Muscular Atrophy (SMA) who are on a stable regimen of nusinersen, risdiplam, or have a history of onasemnogene abeparvovec-xioi, compared to a placebo group. Secondary endpoints include changes from baseline in the Revised Upper Limb Module (RULM) and the Hammersmith Functional Motor Scale Expanded (RHS) at Week 48. Additionally, safety and tolerability will be assessed through changes in lean body mass and bone mineral density via DXA scans, Tanner staging for puberty monitoring, and monitoring of injection acceptability. The frequency of unique subjects with new or worsening laboratory abnormalities, treatment-related adverse events, serious adverse events, and adverse events leading to discontinuation will also be evaluated. Trough plasma concentrations of taldefgrobep alfa and pharmacokinetic parameters will be estimated using population PK modeling. These assessments will be conducted at specified time points, with the primary analysis occurring at Week 48.