ITVISMA

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. ( 1 )

2 DOSAGE AND ADMINISTRATION For single-dose intrathecal injection only. ( 2 ) The recommended dose of ITVISMA is 1.2 × 10 14 vector genomes (vg). ( 2.2 ) Administer ITVISMA as an intrathecal bolus injection over approximately 1 to 2 minutes. ( 2.4 ) Postpone ITVISMA in patients with infections until the infection has resolved and the patient is clinically stable. ( 2.1 ) Starting one day prior to ITVISMA injection, administer systemic corticosteroids equivalent to oral prednisolone at 1 mg/kg of body weight per day for a total of 30 days. At the end of the 30-day period, check liver function by clinical examination and by laboratory testing. For patients with unremarkable findings, taper the corticosteroid dose gradually over the next 28 days. If liver function abnormalities persist, continue systemic corticosteroids (equivalent to oral prednisolone at 1 mg/kg/day) until findings become unremarkable, and then taper the corticosteroid dose gradually over the next 28 days or longer if needed. Do not stop systemic corticosteroids abruptly. ( 2.2 ) If at any time patients do not respond adequately to the equivalent of 1 mg/kg/day oral prednisolone, based on the patient’s clinical course, prompt consultation with a gastroenterologist or hepatologist and adjustment to the recommended corticosteroid regimen may be considered. ( 2.2 ) 2.1 Critical Dosing Information For single-dose intrathecal injection only. Patients previously treated with ZOLGENSMA (onasemnogene abeparvovec-xioi) should not be treated with ITVISMA [see Clinical Pharmacology (12.1)] . ITVISMA should only be administered intrathecally using a lumbar puncture by healthcare professionals (e.g., interventional radiologist or neurologist) experienced in performing lumbar punctures. Prior to ITVISMA injection: Due to the increased risk of serious systemic immune response, administer ITVISMA to patients who are clinically stable in their overall baseline health status (e.g., hydration and nutritional status, absence of infection, respiratory status) prior to administration. Postpone ITVISMA in patients with active or recent infections, until the infection has resolved, and the patient is clinically stable. Clinical signs or symptoms of infection should not be evident at the time of ITVISMA injection. Assess vaccination status. Vaccination status should be up-to-date prior to ITVISMA administration. Recommend seasonal prophylaxis against respiratory syncytial virus (RSV). Assess liver function (clinical examination and laboratory testing including aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, prothrombin time, partial thromboplastin time (PTT), international normalized ratio (INR), and total bilirubin) [see Warnings and Precautions (5.1), Use in Specific Populations (8.6)] . Obtain creatinine and complete blood count (including hemoglobin and platelet count) [see Warnings and Precautions (5.2, 5.4)] . Perform baseline testing for the presence of anti-AAV9 antibodies. One day prior to ITVISMA injection, begin administration of systemic corticosteroids equivalent to oral prednisolone at 1 mg per kg of body weight per day (mg/kg/day) for a total of 30 days. Do not stop systemic corticosteroids abruptly. After the 30-day period, taper prednisolone (or equivalent) as needed according to the clinical status and liver function testing [see Warnings and Precautions (5.1, 5.2)] . See Table 1 for the recommended corticosteroid regimen. Do not re-administer ITVISMA. 2.2 Dose The recommended dose of ITVISMA is 1.2 × 10 14 vector genomes (vg). Table 1 includes the recommended corticosteroid regimen prior to and following ITVISMA injection. If at any time patients do not respond adequately to the equivalent of 1 mg/kg/day oral prednisolone, based on the patient’s clinical course, obtain prompt consultation with a gastroenterologist or hepatologist and consider adjustment to the recommended corticosteroid regimen, including increased dose, longer duration or prolongation of corticosteroid taper [see Warnings and Precautions (5.1)] . If oral corticosteroid therapy is not tolerated or not effective, consider intravenous corticosteroids, as clinically indicated. Table 1: Recommended Corticosteroid Regimen Pre- and Post- ITVISMA Injection Pre-Injection - 24 hours prior to ITVISMA injection Oral prednisolone 1 mg/kg/day (or equivalent) Post-Injection - 30 days (including the day of ITVISMA administration) Oral prednisolone 1 mg/kg/day (or equivalent) Followed by 28 days: For patients with unremarkable findings (normal clinical exam, total bilirubin, and ALT and AST levels below 2 × ULN) or For patients with liver function abnormalities at the end of the 30 day period: continue until the AST and ALT values are both below 2 × ULN and all other assessments return to normal range, and then taper the corticosteroid dose over the next 28 days or longer if needed . Systemic corticosteroids should be tapered gradually Taper prednisolone (or equivalent) Systemic corticosteroids (equivalent to oral prednisolone 1 mg/kg/day) Systemic corticosteroids should be tapered gradually 2.3 Preparation Required supplies and materials (not supplied) Needle for withdrawal Syringe Syringe cap Spinal needle The supplies and materials compatible with ITVISMA are listed in Table 2. Device components must be indicated for intrathecal or neuraxial use. Ensure all device components use the same connector type. Incompatible device connections may result in dose loss during administration. Table 2: Component Materials Compatible With ITVISMA a Not to be manufactured with Polyvinylchloride (PVC), Bisphenol-A (BPA), Bis(2- ethylhexyl) phthalate (DEHP) or Latex Component Material of Construction 18G to 19G Needle for withdrawal, maximum 1.5” long Stainless steel 5mL to 10mL Syringe a Polypropylene Syringe cap a Polypropylene or Polyethylene or Methacrylate-Acrylonitrile-Butadiene-Styrene 22G to 27G Spinal needle, maximum 150mm long Stainless steel Vial Preparation: ITVISMA should be prepared aseptically. Thaw ITVISMA in the refrigerator for approximately 4 hours, or at room temperature for approximately 1 hour. If thawed in the refrigerator, remove ITVISMA from refrigerator on day of dosing. Do not use ITVISMA unless thawed. Prior to intrathecal injection, ITVISMA should be brought to room temperature. When thawed, ITVISMA is a clear to slightly opaque, colorless to faint white liquid, free of particles. After withdrawal of ITVISMA from the vial, a visual inspection is required. DO NOT use if particulates, cloudiness, or discoloration are visible. DO NOT SHAKE. Immediately prior to dosing, draw the content from the vial into the syringe, remove air from syringe, confirm the dose volume of 3 mL in the syringe, cap syringe and deliver to patient injection location. Once dose is drawn into the syringe, it may be held in the refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours, including a 5-hour maximum time out-of-refrigeration allowance within the 24-hour period. Discard the vector-containing syringe if not injected within this time period. DO NOT REFREEZE. Procedural Preparation Instructions: Consider sedation if indicated by the patient’s clinical status. Consider imaging techniques to guide intrathecal injection of ITVISMA. Evaluate patient prior to and after intrathecal injection for conditions that may contraindicate lumbar puncture or increase procedural risk to prevent serious complications. 2.4 Administration Intrathecal Injection Instructions: Prior to administration, remove 3 mL of cerebrospinal fluid (CSF) using a lumbar puncture needle to create space for injection volume. Administer ITVISMA as an intrathecal bolus injection over approximately 1 to 2 minutes through the lumbar puncture needle. Place patient in Trendelenburg position (head down at 30 degrees for 15 minutes). Adjust patient positioning and duration based on the patient’s clinical status to enhance distribution. Follow standard post-lumbar puncture care protocols. Monitoring Following ITVISMA Injection: Liver function (AST, ALT, total bilirubin) weekly for the month after ITVISMA injection and during the corticosteroid taper period (over the next 28 days or longer if needed). If the patient is clinically stable with unremarkable findings (normal clinical exam, total bilirubin, and ALT and AST levels below 2 × ULN) at the end of the corticosteroid taper period, continue to monitor liver function every other week for another month [see Warnings and Precautions (5.1)] . Platelet counts weekly for the first month and as clinically indicated until platelet counts return to baseline [see Warnings and Precautions (5.2)] .

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Hepatotoxicity: Prior to ITVISMA injection, assess liver function of patients by clinical examination and laboratory testing. Continue to monitor liver function for at least 3 months after injection, and at other times as clinically indicated. ( 2.1 , 2.4 , 5.1 ) Thrombocytopenia: Monitor platelet counts before ITVISMA injection, and at least weekly for the first month and as clinically indicated until platelet counts return to baseline. ( 2.1 , 2.4 , 5.2 ) Peripheral Sensory Neuropathy: Consider complete neurologic evaluation and other testing and/or symptom management based on the patient's clinical presentation. ( 5.3 ) Thrombotic Microangiopathy (TMA): Prompt attention to signs and symptoms of TMA is advised, as TMA can result in life-threatening or fatal outcomes. If clinical signs, symptoms and/or laboratory findings occur, consult a hematologist and/or nephrologist immediately to manage as clinically indicated. ( 5.4 ) Elevated Cardiac Troponin I: Increases in cardiac troponin I have occurred following ITVISMA injection. Consider cardiac evaluation after ITVISMA administration and consult a cardiologist as needed. ( 5.5 ) AAV Vector Integration and Risk of Tumorigenicity: There is a theoretical risk of tumorigenicity due to integration of AAV vector DNA into the genome. Report cases of tumors in patients who received ITVISMA, to Novartis Gene Therapies, Inc. ( 5.6 ) 5.1 Hepatotoxicity Hepatotoxicity, with elevated ALT and/or AST levels, has occurred with ITVISMA [see Adverse Reactions (6.1)] . Patients with preexisting hepatic impairment or acute hepatic viral infection may be at higher risk of liver injury. In order to mitigate potential aminotransferase elevations, administer systemic corticosteroid before and after ITVISMA injection. Immune-mediated hepatotoxicity may require adjustment of the corticosteroid treatment regimen, including longer duration, increased dose, or prolongation of the corticosteroid taper [see Dosage and Administration (2.2)] . Prior to ITVISMA injection, assess liver function by clinical examination and laboratory testing. Continue to monitor liver function for at least 3 months after ITVISMA administration, and at other times as clinically indicated. Monitor AST, ALT and total bilirubin weekly for the month after ITVISMA administration and during the corticosteroid taper period. If the patient is clinically stable with unremarkable findings at the end of the corticosteroid taper period, continue to monitor liver function every other week for another month. Tapering of systemic corticosteroids should not be considered until AST/ALT levels are less than 2 × ULN [see Dosage and Administration (2.1, 2.4)] . Monitor patients with worsening liver function test results and/or signs or symptoms of acute illness (e.g., vomiting, deterioration in health). In case hepatic injury is suspected, further testing is recommended (e.g., albumin, prothrombin time, partial thromboplastin time (PTT) and international normalized ratio (INR)). Promptly consult with a gastroenterologist or hepatologist, as necessary. 5.2 Thrombocytopenia Transient decreases in platelet counts were observed within the first week after ITVISMA administration [see Adverse Reactions (6.1)] . The platelets counts are expected to return to baseline two weeks following ITVISMA injection. Monitor platelet counts before ITVISMA injection and on a regular basis afterwards (at least weekly for the first month and as clinically indicated until platelet counts return to baseline) [see Dosage and Administration (2.1, 2.4)] . 5.3 Peripheral Sensory Neuropathy Peripheral sensory neuropathy has occurred with ITVISMA administration [see Adverse Reactions (6.1)] . Signs and symptoms may include numbness, tingling, prickling, or pain in the arms, hands, legs and/or feet, with onset seen at approximately three weeks post-injection in clinical studies. Consider complete neurologic evaluation and other testing and/or symptom management based on the patient's clinical presentation. Inform patients and caregivers about the signs and symptoms of peripheral sensory neuropathy, and advise patients and caregivers to notify their physician promptly if such symptoms occur. 5.4 Thrombotic Microangiopathy Thrombotic microangiopathy (TMA) may occur with ITVISMA administration. TMA is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury. Concurrent immune system activation (e.g., infections, vaccinations) may be a contributing factor. Prompt attention to signs and symptoms of TMA is advised, as TMA can result in life-threatening or fatal outcomes. Monitor platelet counts on a regular basis following ITVISMA injection [see Warnings and Precautions (5.2)] , as well as signs and symptoms of TMA, such as hypertension, bruising easily, seizures, or decreased urine output. In case these signs and symptoms occur in the presence of thrombocytopenia, further diagnostic evaluation for hemolytic anemia and renal dysfunction should be promptly undertaken. If clinical signs, symptoms and/or laboratory findings consistent with TMA occur, consult a hematologist and/or nephrologist immediately to manage TMA as clinically indicated. 5.5 Elevated Cardiac Troponin I Increases in cardiac troponin I levels have occurred following ITVISMA administration without clinical sequelae [see Adverse Reactions (6.1)] . Cardiac toxicity was observed in animal studies [see Nonclinical Toxicology (13.2)] . Consider cardiac evaluation after ITVISMA administration and consult a cardiologist as needed. 5.6 AAV Vector Integration and Risk of Tumorigenicity There is a theoretical risk of tumorigenicity due to integration of AAV vector DNA into the genome. ITVISMA is composed of a recombinant, non-replicating AAV9 vector whose DNA persists largely in episomal form. Random integration of recombinant AAV-vector DNA into human DNA has been reported with AAV gene therapies. The clinical relevance of individual integration events is unknown, but it is acknowledged that individual integration events could potentially contribute to a risk of tumorigenicity. If a tumor develops in a patient receiving ITVISMA, health care providers should contact and report the tumor to Novartis Gene Therapies, Inc. at 1-833-828-3947.

7 DRUG INTERACTIONS Adjust patient’s vaccination schedule to accommodate concomitant corticosteroid administration prior to and following ITVISMA injection [see Dosage and Administration (2.1)] . Certain vaccines, such as measles, mumps, and rubella (MMR) and varicella, are contraindicated for patients on a substantially immunosuppressive steroid dose (i.e., ≥ 2 weeks of daily receipt of 20 mg or 2 mg/kg body weight of prednisone or equivalent). Adjust patient’s vaccination schedule to accommodate concomitant corticosteroid administration prior to and following ITVISMA injection. ( 7 )

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

8.1 Pregnancy Risk Summary There are no clinical studies in pregnant women to inform a product-associated risk. There are no available data in animal embryo-fetal development studies with ITVISMA. It is not known whether ITVISMA has the potential to be transferred to the fetus. Therefore, women who are pregnant or desire to become pregnant should only be treated with ITVISMA after a thorough benefit-risk evaluation. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.