Evaluation of Clinical Outcomes of Nusinersen in Patients with Spinal Muscular Atrophy Post-Onasemnogene Abeparvovec Administration

The primary objective of this study is to evaluate the **clinical outcomes** following treatment with **nusinersen** in participants with **Spinal Muscular Atrophy (SMA)** who previously received **onasemnogene abeparvovec**. This evaluation is clinically relevant as it aims to determine the efficacy of nusinersen in improving or maintaining motor function and other health outcomes in this specific patient population, potentially guiding future treatment strategies for SMA.

The secondary objectives of this study are to evaluate the **safety and tolerability**, as well as the **clinical outcomes** and **pharmacodynamics (PD)** of nusinersen treatment in participants with SMA who previously received onasemnogene abeparvovec. These assessments are crucial for understanding the overall benefit-risk profile of nusinersen in this context, ensuring that the treatment is both effective and safe for long-term use in managing SMA.

The clinical trial involves a total of **21 participants** diagnosed with **Spinal Muscular Atrophy** (SMA). The study population includes both male and female subjects, with an age range of up to 36 months at the time of the first dose of nusinersen. Participants were selected based on genetic documentation of 5q SMA homozygous gene survival motor neuron 1 (SMN1) deletion or mutation, or compound heterozygous mutation. The trial includes individuals who have previously received onasemnogene abeparvovec, with specific criteria for subgroups based on age and treatment history. The population is considered vulnerable, and participants must have a suboptimal clinical status as determined by the investigator. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the clinical outcomes of **nusinersen** treatment in participants with **Spinal Muscular Atrophy** (SMA) who have previously received onasemnogene abeparvovec. This is a Phase 4, randomized, double-blind, controlled study. The trial is expected to last until October 2025, with participant involvement spanning up to 778 days. The study will assess both primary and secondary endpoints, including the Total Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestones Score and various safety and efficacy parameters such as adverse events, changes in clinical laboratory parameters, and motor milestone achievements.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as genetic documentation of 5q SMA and previous treatment with onasemnogene abeparvovec. Follow-up visits will be conducted at regular intervals to monitor the participants' health status, assess treatment efficacy, and record any adverse events. The end-of-study visit will conclude the trial, where final assessments will be made to evaluate the long-term effects of the treatment.

The expected length of participant involvement is approximately 778 days, with the possibility of early termination if certain conditions arise, such as significant adverse events or withdrawal of consent. The trial will adhere to strict protocols to ensure the safety and well-being of all participants, with regular monitoring and assessments throughout the study duration.

The clinical trial involves the administration of **Spinraza** (nusinersen), a **solution for injection** specifically formulated for the treatment of **spinal muscular atrophy** (SMA). Spinraza is provided as a 12 mg solution for injection, with the active substance being **nusinersen**, a nucleic acid-based compound. The pharmaceutical form is a solution intended for **intrathecal use**, which involves administration directly into the spinal canal. The maximum daily and total dose is 12 mg, and the treatment period can extend up to 659 days. The product is manufactured by Biogen Netherlands B.V. and is classified under the ATC code M09AX07. Spinraza is designated as an orphan drug, indicating its use in rare diseases.

In this study, participants who have previously received onasemnogene abeparvovec will be treated with nusinersen to evaluate clinical outcomes. The trial does not include any non-experimental treatments such as a placebo or comparator treatment. Compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol. The study aims to assess the efficacy and safety of nusinersen in this specific patient population, contributing valuable data to the understanding of its therapeutic potential in SMA management.

The efficacy of nusinersen in patients with **Spinal Muscular Atrophy** (SMA) will be assessed through a series of primary and secondary endpoints. The primary endpoint is the Total Hammersmith Infant Neurological Examination (HINE) Section 2 Motor Milestones Score, which will be measured up to Day 778. This endpoint evaluates the motor milestone achievements in participants, providing a direct measure of clinical improvement.

Secondary endpoints include a variety of measures to assess both safety and efficacy. These include the number of participants with adverse events (AEs) and serious adverse events (SAEs), changes from baseline in clinical laboratory parameters, electrocardiograms (ECGs), and vital signs, all measured up to Day 778. Additionally, the number of participants achieving motor milestones as per World Health Organization (WHO) criteria, and changes from baseline in scores from the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), Hammersmith Functional Motor Scale - Expanded (HFMSE), and Revised Upper Limb Module (RULM) will be evaluated. The time to death or permanent ventilation is also a critical endpoint. Furthermore, changes from baseline in cerebrospinal fluid (CSF) and plasma levels of Neurofilament Light Subunit (NF-L) will be assessed, with CSF levels measured up to Day 659 and plasma levels up to Day 778.