Evaluation of High-Dose Nusinersen in Spinal Muscular Atrophy Patients Previously Treated with Risdiplam: A Phase 3b Clinical Trial

The primary objective of this study is to evaluate **motor function** following treatment with higher dose (HD) **nusinersen** in participants with **Spinal Muscular Atrophy** (SMA) who have previously been treated with **risdiplam**. This evaluation is clinically relevant as it aims to determine the efficacy of HD nusinersen in improving motor function, which is a critical aspect of managing SMA, a condition characterized by progressive muscle weakness and atrophy.

The secondary objective is to assess the safety and tolerability of HD nusinersen in the same cohort of participants. Understanding the safety profile and tolerability is essential for ensuring that the treatment is not only effective but also safe for long-term use in patients with SMA.

The clinical trial involves a total of **23 participants** diagnosed with **Spinal Muscular Atrophy** (SMA). The study population includes both male and female subjects, aged between **15 to 50 years**, who are nonambulatory and have a body weight greater than 20 kg. Participants were selected based on genetic documentation of 5q SMA homozygous survival motor neuron-1 (SMN1) gene deletion or mutation, or compound heterozygous mutation. They must have been previously treated with risdiplam and are willing to transition to HD nusinersen treatment. The trial includes individuals who have experienced later-onset SMA with symptom onset after 6 months of age. Participants are required to have received oral risdiplam for at least 6 months if they are nusinersen-naive, or have stopped nusinersen for at least 16 months and been on risdiplam for at least 12 months if they are nusinersen-experienced. The study population is capable of performing age-appropriate functional assessments and meets specific Revised Upper Limb Module (RULM) score criteria. The trial does not exclude based on gender, and it includes a vulnerable population, ensuring a comprehensive evaluation of motor function following the treatment regimen.

The clinical trial is designed to evaluate the efficacy and safety of higher dose **nusinersen** in patients with **Spinal Muscular Atrophy** (SMA) who have previously been treated with risdiplam. This is a Phase 3b, randomized, double-blind, controlled study. The trial is expected to last until July 22, 2027, with recruitment having started on November 22, 2021. Participants will be involved in the study for a maximum treatment period of 735 days, with the primary endpoint being the change in the Total Revised Upper Limb Module (RULM) Score up to Day 855. Secondary endpoints include the number of participants with adverse events and changes in clinical laboratory parameters up to Day 1695.

The study involves several key visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as genetic documentation of 5q SMA, willingness to stop risdiplam, and ability to start treatment with higher dose nusinersen. Participants must be aged between 15 and 50 years, have a body weight greater than 20 kg, and meet specific functional assessment criteria. Follow-up visits will be conducted to monitor motor function and safety, with assessments including clinical laboratory tests, electrocardiograms, and vital signs. The end-of-study visit will conclude the participant's involvement, assessing the overall outcomes and any long-term effects of the treatment.

Participants may be terminated early from the study if they experience significant adverse events, fail to comply with study procedures, or withdraw consent. The trial is conducted under strict regulatory guidelines to ensure the safety and well-being of all participants. The investigational product, SPINRAZA, is administered via intrathecal injection, with doses not exceeding 50 mg per administration. The study aims to provide valuable insights into the potential benefits of higher dose nusinersen for individuals with SMA, contributing to the advancement of therapeutic options for this condition.

The clinical trial involves the administration of **SPINRAZA 28 mg**, a **solution for injection** containing the active substance **nusinersen**. Nusinersen is a nucleic acid-based therapeutic agent, specifically an antisense oligonucleotide targeted to the SMN2 gene. The pharmaceutical form is a solution for injection, and the route of administration is intrathecal use. The maximum daily dose is 50 mg, with a total treatment period not exceeding 735 days. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

Additionally, the trial includes the use of **SPINRAZA 50 mg**, which also contains the active substance **nusinersen**. This formulation is similarly a **solution for injection** and is administered intrathecally. The maximum daily dose for this formulation is also 50 mg, with the same maximum treatment period of 735 days. Both formulations are produced by Biogen Idec Research Limited and are classified as orphan drugs, designated under the number EU/3/12/976. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Compliance with the dosing schedule is closely monitored to ensure the integrity of the trial results.

The efficacy of the clinical trial evaluating higher dose **nusinersen** in patients with Spinal Muscular Atrophy (SMA) will be assessed primarily through the change in the Total Revised Upper Limb Module (RULM) Score. This primary endpoint will be measured up to Day 855 of the trial. The RULM is a validated scale used to evaluate motor function, specifically focusing on upper limb capabilities, which is crucial for assessing the impact of the treatment on SMA patients.

Secondary endpoints include the number of participants experiencing adverse events (AEs) and serious adverse events (SAEs), as well as changes in clinical laboratory parameters, electrocardiogram (ECG) readings, vital signs, and pulse oximetry from baseline. These secondary endpoints will be monitored up to Day 1695. The collection and analysis of these efficacy parameters will be conducted at specified time points throughout the trial to ensure comprehensive evaluation of the treatment's impact on the participants' health and motor function.