1 INDICATIONS AND USAGE ITVISMA is indicated for the treatment of spinal muscular atrophy (SMA) in adult and pediatric patients 2 years of age and older with confirmed mutation in survival motor neuron 1 (SMN1) gene.

ITVISMA is an adeno-associated virus (AAV) vector-based gene therapy indicated for the treatment of spinal muscular atrophy (SMA) in adult and pediatric patients 2 years of age and older with confirmed mutation in SMN1 gene.

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6 ADVERSE REACTIONS The most common adverse reactions that occurred in at least 10% of patients were upper respiratory tract infection, upper gastrointestinal symptoms, pyrexia, and headache.

( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Novartis Gene Therapies at 1-833-828-3947 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another product and may not reflect the rates observed in practice.

The safety data described in this section reflects exposure of ITVISMA in two clinical studies, Study 1, a randomized, sham-controlled study which evaluated the safety of ITVISMA in 126 patients with spinal muscular atrophy (SMA) and Study 2, an open-label-single arm study which evaluated safety of ITVISMA in 27 patients with SMA who were previously treated with nusinersen (at least 4 months washout) or risdiplam (at least 15 days washout).

In Study 1, a total of 75 patients received a single intrathecal injection of ITVISMA at a fixed dose of 1.2 x 10 14 vg and 51 patients underwent a sham-procedure [see Clinical Studies (14)] .

In Study 2, a total of 27 patients received a single intrathecal injection of ITVISMA at a fixed dose of 1.2 x 10 14 vg.

The patients were followed for a duration of 52 weeks for both studies.

In Study 1, serious adverse reactions were reported in four patients (5%) including elevated liver enzymes (n=1), sensory disturbance (n=2), and vomiting (n=1).

The most frequent adverse reactions occurring in ≥ 2% of patients in Study 1 are summarized in Table 3 below.

Table 3: Adverse Reactions Occurring in ≥2% of Patients or with higher frequency in ITVISMA-treated Patients compared to Sham group in Study 1 Adverse reactions ITVISMA Sham (N = 75), n (%) (N = 51), n (%) * Is a composite that includes multiple related terms a) Two patients had ALT elevations of 20 times the upper limit of normal (ULN) b) Signs and symptoms that may be suggestive of dorsal root ganglion (DRG) toxicity occurred within 3 weeks of ITVISMA injection and stabilized but remained unresolved at the end of study period.

c) Occurred 154 days after the sham procedure and resolved after 15 days without intervention.

Upper respiratory tract infection * 31 (41) 15 (29) Pyrexia 19 (25) 12 (24) Upper gastrointestinal symptoms * 20 (27) 8 (16) Hepatic enzyme increased * 6 (8) a 5 (10) Headache 8 (11) 2 (4) Dizziness 4 (5) 1 (2) Pain in extremity 3 (4) 1 (2) Thrombocytopenia * 3 (4) 0 Sensory disturbance * 2 (3) b 1 (2) c The safety evaluated in Study 2 did not identify any additional safety events with ITVISMA administration.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ZOLGENSMA, a similar product containing the same active ingredient (onasemnogene abeparvovec) administered intravenously.

Because these reactions are reported voluntarily, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic System Disorders : thrombotic microangiopathy Hepatobiliary Disorders : acute liver failure (fatal and non-fatal), acute liver injury General Disorders and Administration Site Conditions : pyrexia, infusion-related reactions Investigations : troponin increased