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Description for Zolgensma

ZOLGENSMA is a suspension of an adeno-associated viral vector-based gene therapy for intravenous infusion. It is a recombinant self-complementary AAV9 containing a transgene encoding the human survival motor neuron (SMN) protein, under the control of a cytomegalovirus enhancer/chicken-β-actin hybrid promoter.

ZOLGENSMA has a nominal concentration of 2.0 × 1013 vg/mL. Each vial contains an extractable volume of not less than either 5.5 mL or 8.3 mL and the excipients 20 mM Tris (pH 8.0), 1 mM magnesium chloride (MgCl2), 200 mM sodium chloride (NaCl) and 0.005% poloxamer 188. ZOLGENSMA is packaged as a sterile suspension and contains no preservative.

Uses for Zolgensma

ZOLGENSMA is an adeno-associated virus (AAV) vector-based gene therapy indicated for the treatment of pediatric patients less than 2 years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene.

Limitations Of Use

• The safety and effectiveness of repeat administration of ZOLGENSMA have not been evaluated [see ADVERSE REACTIONS].
• The use of ZOLGENSMA in patients with advanced SMA (e.g., complete paralysis of limbs, permanent ventilator-dependence) has not been evaluated [see Clinical Studies].

Dosage for Zolgensma

For single-dose intravenous infusion only.

Dose And Administration

The recommended dose of ZOLGENSMA is 1.1 x 1014 vector genomes per kilogram (vg/kg) of body weight.

Table 1: Dosing

Patient weight range (kg)	Dose volumea (mL)
2.6 – 3.0	16.5
3.1 – 3.5	19.3
3.6 – 4.0	22.0
4.1 – 4.5	24.8
4.6 – 5.0	27.5
5.1 – 5.5	30.3
5.6 – 6.0	33.0
6.1 – 6.5	35.8
6.6 – 7.0	38.5
7.1 – 7.5	41.3
7.6 – 8.0	44.0
8.1 – 8.5	46.8
8.6 – 9.0	49.5
9.1 – 9.5	52.3
9.6 – 10.0	55.0
10.1 – 10.5	57.8
10.6 – 11.0	60.5
11.1 – 11.5	63.3
11.6 – 12.0	66.0
12.1 – 12.5	68.8
12.6 – 13.0	71.5
13.1 – 13.5	74.3
13.6 – 14.0	77.0
14.1 – 14.5	79.8
14.6 – 15.0	82.5
15.1 – 15.5	85.3
15.6 – 16.0	88.0
16.1 – 16.5	90.8
16.6 – 17.0	93.5
17.1 – 17.5	96.3
17.6 – 18.0	99.0
18.1 – 18.5	101.8
18.6 – 19.0	104.5
19.1 – 19.5	107.3
19.6 – 20.0	110.0
20.1 – 20.5	112.8
20.6 – 21.0	115.5
aDose volume is calculated using the upper limit of the patient weight range for pediatric patients less than 2 years of age between 2.6 kg and 21.0 kg.

• Prior to ZOLGENSMA infusion:
  • Due to the increased risk of serious systemic immune response, administer ZOLGENSMA to patients who are clinically stable in their overall baseline health status (e.g., hydration and nutritional status, absence of infection) prior to infusion. Postpone ZOLGENSMA in patients with 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 ZOLGENSMA infusion [see WARNINGS AND PRECAUTIONS , PATIENT INFORMATION].
  • Assess liver function [see BOX WARNING, Laboratory Testing And Monitoring To Assess Safety, WARNINGS AND PRECAUTIONS, Use In Specific Populations].
  • Obtain creatinine and complete blood count (including hemoglobin and platelet count) [see Laboratory Testing And Monitoring To Assess Safety, WARNINGS AND PRECAUTIONS].
  • Perform baseline testing for the presence of anti-AAV9 antibodies [see Laboratory Testing And Monitoring To Assess Safety, ADVERSE REACTIONS].
• One day prior to ZOLGENSMA infusion, 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.
• Administer ZOLGENSMA as a single-dose intravenous infusion through a venous catheter.

Follow the steps below for infusion

1. Place a primary catheter into a vein (generally a peripheral vein in the arm or leg). Insertion of a back-up catheter is recommended.
2. Program syringe pump for saline priming, or prime tubing manually with saline.
3. Administer ZOLGENSMA as a slow infusion over 60 minutes. DO NOT INFUSE AS AN INTRAVENOUS PUSH OR BOLUS.
4. Flush line with saline following completion of infusion.

• Monitor liver function by clinical examination and by laboratory testing on a regular basis, and at other times as clinically indicated [see Laboratory Testing And Monitoring To Assess Safety].
  • At the end of the 30-day period of systemic corticosteroid treatment, check liver status clinically and by assessing alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, prothrombin time, and international normalized ratio (INR).
  • Promptly assess and closely monitor patients with worsening liver function test results and/or signs or symptoms of acute illness (e.g., vomiting, deterioration in health) [see WARNINGS AND PRECAUTIONS].
  • For patients with unremarkable findings (normal clinical exam, total bilirubin, prothrombin time, and INR and ALT and AST levels below 2 x upper limit of normal [ULN]): Taper the corticosteroid dose gradually over the next 28 days. Do not stop systemic corticosteroids abruptly. [see WARNINGS AND PRECAUTIONS].
  • If liver function abnormalities persist, continue systemic corticosteroids (equivalent to oral prednisolone at 1 mg/kg/day) until AST and ALT values are both below 2 x ULN and all other assessments return to normal range, and then taper the corticosteroid dose gradually over the next 28 days or longer if needed. Do not stop systemic corticosteroids abruptly [see WARNINGS AND PRECAUTIONS].
  • If liver function abnormalities continue to persist ≥ 2 x ULN after the 30-day period of systemic corticosteroids, promptly consult a pediatric gastroenterologist or hepatologist [see WARNINGS AND PRECAUTIONS].
  • If oral corticosteroid therapy is not tolerated, consider intravenous corticosteroids as clinically indicated [see WARNINGS AND PRECAUTIONS].

Preparation

• Thaw ZOLGENSMA before use. The contents of the ZOLGENSMA kit will thaw in approximately 16 hours if placed in a refrigerator, or in approximately 6 hours if placed at room temperature. If thawed in a refrigerator, remove from refrigerator on day of dosing.
• When thawed, ZOLGENSMA is a clear to slightly opaque, colorless to faint white liquid, free of particles. Visually inspect vials for particulate matter and discoloration prior to infusion. Do not use vials if particulates or discoloration are present.
• DO NOT SHAKE.
• Draw the appropriate dose volume from all vials into a syringe, remove air from the syringe, cap the syringe, and deliver the syringe at room temperature to the patient infusion location.
• Use ZOLGENSMA within 8 hours of drawing into syringe. Discard the vector-containing syringe if the drug is not infused within the 8-hour timeframe.
• DO NOT REFREEZE.

Laboratory Testing And Monitoring To Assess Safety

Perform baseline anti-AAV9 antibody testing prior to ZOLGENSMA infusion. Retesting may be performed if anti-AAV9 antibody titers are reported as > 1:50 [see Dose And Administration].

Conduct the following tests at baseline and as directed below [see WARNINGS AND PRECAUTIONS]:

• Liver function (clinical exam, AST, ALT, total bilirubin, albumin, prothrombin time, partial thromboplastin time [PTT], and INR) at baseline. Monitor liver function (AST, ALT, total bilirubin, prothrombin time, INR) weekly for the first month after ZOLGENSMA infusion and during the corticosteroid taper period (28 days or longer if needed). If the patient is clinically stable with unremarkable findings (normal clinical exam, total bilirubin, and prothrombin and INR results, and ALT and AST levels below 2 x ULN) at the end of the corticosteroid taper period, continue to monitor liver function every other week for another month.
• Platelet counts weekly for the first month, and then every other week for the second and third months, until platelet counts return to baseline.

HOW SUPPLIED

Dosage Forms And Strengths

ZOLGENSMA is a suspension for intravenous infusion.

ZOLGENSMA is provided in a kit containing 2 to 14 vials. Vials are provided in 2 fill volumes: 5.5 mL or 8.3 mL.

ZOLGENSMA has a nominal concentration of 2.0 x 1013 vg/mL, and each vial contains an extractable volume of not less than either 5.5 mL or 8.3 mL.

The intravenous dosage is determined by patient body weight, with a recommended dose of 1.1 x 1014 vg/kg for pediatric patients.

ZOLGENSMA is shipped frozen (≤ -60°C [-76°F]) in 10 mL vials with 2 fill volumes (either 5.5 mL or 8.3 mL).

ZOLGENSMA is provided as a customized kit to meet dosing requirements for each patient [see DOSAGE AND ADMINISTRATION], with each kit containing:

• Two (2) to fourteen (14) vials of ZOLGENSMA (see below)
• One alcohol wipe per vial

Kit sizes and National Drug Codes (NDC) are provided in Table 3.

Table 3: ZOLGENSMA Kit Sizes

Patient weight (kg)	5.5 mL viala	8.3 mL vialb	Total vials per kit	NDC number
2.6 – 3.0	0	2	2	71894-120-02
3.1 – 3.5	2	1	3	71894-121-03
3.6 – 4.0	1	2	3	71894-122-03
4.1 – 4.5	0	3	3	71894-123-03
4.6 – 5.0	2	2	4	71894-124-04
5.1 – 5.5	1	3	4	71894-125-04
5.6 – 6.0	0	4	4	71894-126-04
6.1 – 6.5	2	3	5	71894-127-05
6.6 – 7.0	1	4	5	71894-128-05
7.1 – 7.5	0	5	5	71894-129-05
7.6 – 8.0	2	4	6	71894-130-06
8.1 – 8.5	1	5	6	71894-131-06
8.6 – 9.0	0	6	6	71894-132-06
9.1 – 9.5	2	5	7	71894-133-07
9.6 – 10.0	1	6	7	71894-134-07
10.1 – 10.5	0	7	7	71894-135-07
10.6 – 11.0	2	6	8	71894-136-08
11.1 – 11.5	1	7	8	71894-137-08
11.6 – 12.0	0	8	8	71894-138-08
12.1 – 12.5	2	7	9	71894-139-09
12.6 – 13.0	1	8	9	71894-140-09
13.1 – 13.5	0	9	9	71894-141-09
13.6 – 14.0	2	8	10	71894-142-10
14.1 – 14.5	1	9	10	71894-143-10
14.6 – 15.0	0	10	10	71894-144-10
15.1 – 15.5	2	9	11	71894-145-11
15.6 – 16.0	1	10	11	71894-146-11
16.1 – 16.5	0	11	11	71894-147-11
16.6 – 17.0	2	10	12	71894-148-12
17.1 – 17.5	1	11	12	71894-149-12
17.6 – 18.0	0	12	12	71894-150-12
18.1 – 18.5	2	11	13	71894-151-13
18.6 – 19.0	1	12	13	71894-152-13
19.1 – 19.5	0	13	13	71894-153-13
19.6 – 20.0	2	12	14	71894-154-14
20.1 – 20.5	1	13	14	71894-155-14
20.6 – 21.0	0	14	14	71894-156-14
aVial nominal concentration is 2.0 x 1013 vg/mL and contains an extractable volume of not less than 5.5 mL. bVial nominal concentration is 2.0 x 1013 vg/mL and contains an extractable volume of not less than 8.3 mL.

Storage And Handling

• Product is shipped and delivered frozen (≤ -60°C [-76°F]) in clear vials.
• Upon receipt, immediately place the kit in a refrigerator at 2°C to 8°C (36°F to 46°F).
• ZOLGENSMA is stable for 14 days from receipt when stored at 2°C to 8°C (36°F to 46°F).
• DO NOT REFREEZE.
• Must use within 14 days of receipt.

Manufactured by, Packed by, Distributed by: Novartis Gene Therapies, Inc. 2275 Half Day Road, Bannockburn, IL 60015 USA. Revised: Feb 2025

Side Effects for Zolgensma

The most common adverse reactions (incidence ≥ 5%) were elevated aminotransferases and vomiting.

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 reflect exposure to ZOLGENSMA in five clinical studies enrolling a total of 68 patients. This includes four prospective open-label clinical trials [NCT03306277 (Study 1), NCT02122952 (Study 2), NCT03505099, NCT04851873 (Study 3)], and one observational long-term follow-up study [NCT03421977]. The patient population in NCT03306277, NCT03505099, and NCT02122952 ranged in age from 0.3 months to 7.9 months at the time of infusion (median age, 3.3 months), with weight range from 3.0 kg to 8.4 kg (median weight, 5.5 kg) [see Clinical Studies].

In an open-label, post-authorization clinical study (Study 3, NCT04851873), safety of ZOLGENSMA was evaluated in 24 children, aged between 1.5 to 9.1 years (median age, 4.9 years), with weight range from ≥ 8.5 kg to ≤ 21 kg (median weight, 15.8 kg). Only one of the 24 patients was under the age of 2 years at the time of ZOLGENSMA administration. Patients in Study 3 had 2 to 4 copies of SMN2. Before treatment with ZOLGENSMA, 21 patients discontinued their previous treatment with nusinersen or risdiplam. The types of adverse reactions observed in Study 3 were consistent with those of Studies 1 and 2. Liver enzyme increases in Study 3 occurred at a higher frequency compared with the previous 4 studies. AST or ALT elevations > 2 × ULN were observed in the majority of patients (23 out of 24 patients), including 21 patients with ALT elevations > 3 × ULN and 5 patients with ALT elevations > 20 × ULN. These patients were clinically asymptomatic and there were no elevations of bilirubin. The AST and ALT elevations were managed with the use of corticosteroids, typically with prolonged duration and/or given at a higher dose [see WARNINGS AND PRECAUTIONS]. Transient decreases in platelet counts, which met the criteria for thrombocytopenia were observed in 20 out of 24 patients. Four patients had platelet counts below 50,000 per μL [see WARNINGS AND PRECAUTIONS].

The most frequent adverse reactions (incidence ≥ 5%) and increases in alanine aminotransferase in the 4 studies (data cut-off date: September 27, 2018) are summarized in Table 2.

Table 2: Adverse Reactions and ALT Increases* Following Treatment With ZOLGENSMA

	Patients n = 44 (3.0-8.4 kg)
Adverse reactions	n (%)
Elevated aminotransferases	12 (27%)
ALT > 3 X ULN	7 (16%)
ALT > 20 X ULN	4 (9%)
Vomiting	3 (7%)
Abbreviations: ULN, upper limit of normal; ALT, alanine aminotransferase. *Laboratory finding.

One death occurred in a patient, who received ZOLGENSMA at the age of 5 months (6 kg), in a completed non-United States clinical trial (NCT03461289). The patient initially presented with respiratory insufficiency 12 days after ZOLGENSMA infusion and was found to have RSV and parainfluenza in respiratory secretions. The patient had episodes of serious hypotension, followed by seizures, and was found to have leukoencephalopathy (brain white matter defects) approximately 30 days after ZOLGENSMA infusion. The patient died after withdrawal of life support 52 days after ZOLGENSMA infusion.

Immunogenicity

In ZOLGENSMA clinical trials, patients were required to have baseline anti-AAV9 antibody titers of ≤ 1:50, measured using an enzyme-linked immunosorbent assay (ELISA). Evidence of prior exposure to AAV9 was uncommon. The safety and efficacy of ZOLGENSMA in patients with anti-AAV9 antibody titers above 1:50 have not been evaluated. Perform baseline testing for the presence of anti-AAV9 antibodies prior to ZOLGENSMA infusion. Retesting may be performed if anti-AAV9 antibody titers are reported as > 1:50 [see DOSAGE AND ADMINISTRATION].

Following ZOLGENSMA infusion, increases from baseline in anti-AAV9 antibody titers occurred in all patients. In Study 2, anti-AAV9 antibody titers reached at least 1:102,400 in every patient, and titers exceeded 1:819,200 in most patients. Re-administration of ZOLGENSMA in the presence of high anti-AAV9 antibody titer has not been evaluated.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ZOLGENSMA. 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 [see WARNINGS AND PRECAUTIONS], thrombocytopenia [see WARNINGS AND PRECAUTIONS]

Hepatobiliary Disorders: acute liver failure (fatal and non-fatal), acute liver injury [see WARNINGS AND PRECAUTIONS]

General Disorders and Administration Site Conditions: pyrexia, infusion-related reactions [see WARNINGS AND PRECAUTIONS]

Investigations: troponin increased [see WARNINGS AND PRECAUTIONS]

Drug Interactions for Zolgensma

Where feasible, adjust a patient’s vaccination schedule to accommodate concomitant corticosteroid administration prior to and following ZOLGENSMA infusion [see DOSAGE AND ADMINISTRATION]. 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). Seasonal RSV prophylaxis is recommended (General Best Practice Guidelines for Immunization [www.cdc.gov/vaccines/hcp/acip-recs/general-recs/downloads/general-recs.pdf], eds2017).

Warnings for Zolgensma

Included as part of the "PRECAUTIONS" Section

Precautions for Zolgensma

Acute Serious Liver Injury, Acute Liver Failure Or Elevated Aminotransferases

Acute serious liver injury, acute liver failure and elevated aminotransferases can occur with ZOLGENSMA. Hepatotoxicity (which may be immune-mediated), generally manifested as elevated ALT and/or AST levels. Acute serious liver injury and acute liver failure, including fatal cases, have been reported with ZOLGENSMA use [see ADVERSE REACTIONS]. In order to mitigate potential aminotransferase elevations, administer systemic corticosteroid to all patients before and after ZOLGENSMA infusion. 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].

Patients with preexisting liver impairment or acute hepatic viral infection may be at higher risk of acute serious liver injury/acute liver failure. Patients with ALT, AST, or total bilirubin levels (except due to neonatal jaundice) > 2 × ULN have not been studied in clinical trials with ZOLGENSMA. Carefully consider the risks and benefits of ZOLGENSMA therapy in patients with preexisting liver impairment.

Although in the clinical trials and in postmarketing experience, asymptomatic aminotransferase elevations were very commonly reported [see ADVERSE REACTIONS], in the managed access program and in the postmarketing setting, cases of acute serious liver injury and acute liver failure, including a few cases with fatal outcomes, have been reported. Some patients have experienced elevations in ALT and AST > 20 × ULN, prolonged prothrombin time and have been symptomatic (e.g., vomiting, jaundice), which required the use of corticosteroids, sometimes with prolonged duration and/or a higher dose. If acute serious liver injury or acute liver failure is suspected, promptly consult a pediatric gastroenterologist or hepatologist.

Prior to ZOLGENSMA infusion, assess liver function by clinical examination and laboratory testing (hepatic aminotransferases [AST and ALT], total bilirubin level, albumin, prothrombin time, PTT, and INR). Continue to monitor liver function (AST, ALT, total bilirubin, prothrombin time, INR) for at least 3 months after ZOLGENSMA infusion, and at other times as clinically indicated.

Promptly assess and closely 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 of albumin, PTT, and INR is recommended.

Monitor liver function weekly for the first month after ZOLGENSMA infusion and during the corticosteroid taper period (28 days or longer if needed). 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 [see DOSAGE AND ADMINISTRATION].

Systemic Immune Response

Due to activation of humoral and cellular immunity following ZOLGENSMA infusion, patients with underlying active infection, either acute (e.g., respiratory, gastrointestinal) or chronic uncontrolled (e.g., chronic active hepatitis B), could be at an increased risk of serious systemic immune response, potentially resulting in more severe clinical courses of the infection. Serious systemic immune response can present with a variety of findings (e.g., high fever, hypotension, etc.). Patients with infection were excluded from participation in ZOLGENSMA clinical trials. Recommend increased vigilance in the prevention, monitoring, and management of infection before and after ZOLGENSMA infusion.

To mitigate the risk of serious and life-threatening systemic immune response, administer ZOLGENSMA to patients who are clinically stable in their overall baseline health status (e.g., hydration and nutritional status, absence of infection) prior to infusion. Postpone ZOLGENSMA in patients with 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 ZOLGENSMA infusion [see DOSAGE AND ADMINISTRATION]. Recommend seasonal prophylaxis against influenza and respiratory syncytial virus (RSV) and vaccination status should be up-to-date prior to ZOLGENSMA administration.

Thrombocytopenia

Transient decreases in platelet counts, some of which met the criteria for thrombocytopenia, were typically observed within the first two weeks after ZOLGENSMA infusion.

Monitor platelet counts before ZOLGENSMA infusion and closely monitor platelet counts within the first two weeks following infusion and on a regular basis afterwards (at least weekly for the first month; every other week for the second and third months or until platelet counts return to baseline) [see DOSAGE AND ADMINISTRATION].

Thrombotic Microangiopathy

Cases of thrombotic microangiopathy (TMA) were reported to occur generally within the first two weeks after ZOLGENSMA infusion in the post-marketing setting [see ADVERSE REACTIONS]. TMA is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury. Concurrent immune system activation (e.g., infections, vaccinations) was identified in some cases.

Prompt attention to signs and symptoms of TMA is advised, as TMA can result in life-threatening or fatal outcomes.

Monitor platelet counts closely within the first two weeks following infusion and on a regular basis afterwards [see Thrombocytopenia], as well as signs and symptoms of TMA, such as hypertension, increased bruising, 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 pediatric hematologist and/or pediatric nephrologist immediately to manage TMA as clinically indicated.

Elevated Troponin I

Increases in cardiac troponin I levels (up to 0.176 mcg/L) have occurred following ZOLGENSMA infusion in clinical trials. Cardiac toxicity was observed in animal studies [see Nonclinical Toxicology]. Consider cardiac evaluation after ZOLGENSMA infusion and consult a cardiologist as needed.

AAV Vector Integration And Risk Of Tumorigenicity

There is a theoretical risk of tumorigenicity due to integration of AAV vector DNA into the genome.

ZOLGENSMA 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 ZOLGENSMA and in published literature about other 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. Cases of tumor have been reported in patients who received ZOLGENSMA post-approval. A causal relationship with ZOLGENSMA has not been established based on tumor analyses. However, in some cases, limited information was available. If a tumor develops in a patient receiving ZOLGENSMA, healthcare providers should contact and report the tumor to Novartis Gene Therapies, Inc. at 1-833-828-3947.

Infusion-Related Reactions

Infusion-related reactions, including hypersensitivity reactions and anaphylaxis, have occurred with ZOLGENSMA infusion [see ADVERSE REACTIONS]. Signs and symptoms may include rash, urticaria, vomiting, dyspnea, respiratory symptoms and/or alterations in heart rate and blood pressure. Monitor patients during and after treatment with ZOLGENSMA. If an infusion-related reaction occurs, interrupt ZOLGENSMA infusion and administer supportive treatment to manage the infusion-related reaction as appropriate. Infusion of ZOLGENSMA may be resumed based on clinical assessment.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No animal studies have been performed to evaluate the effects of onasemnogene abeparvovec on carcinogenesis, mutagenesis, or impairment of fertility.

Use In Specific Populations

Pregnancy

Risk Summary

There are no available data regarding ZOLGENSMA use in pregnant women. No animal reproductive and developmental toxicity studies have been conducted with ZOLGENSMA.

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.

Lactation

Risk Summary

There is no information available on the presence of ZOLGENSMA in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZOLGENSMA and any potential adverse effects on the breastfed child from ZOLGENSMA or from the underlying maternal condition.

There is no information on whether breastfeeding should be restricted in mothers who may be seropositive for anti-AAV9 antibodies.

Pediatric Use

The safety of ZOLGENSMA was studied in pediatric patients who received ZOLGENSMA infusion at age 0.3 to 7.9 months (weight range, 3.0 kg to 8.4 kg). Safety was also studied in Study 3 (post-authorization study) in patients weighing 9.5 kg to 20.2 kg [see ADVERSE REACTIONS].

The efficacy of ZOLGENSMA was studied in pediatric patients who received ZOLGENSMA infusion at age 0.5 to 7.9 months (weight range, 3.6 kg to 8.4 kg) [see Clinical Studies].

Administration of ZOLGENSMA to premature neonates before reaching full-term gestational age is not recommended, because concomitant treatment with corticosteroids may adversely affect neurological development. Delay ZOLGENSMA infusion until the corresponding full-term gestational age is reached.

Hepatic Impairment

ZOLGENSMA therapy should be carefully considered in patients with liver impairment. Cases of acute serious liver injury and acute liver failure have been reported with ZOLGENSMA in patients with preexisting liver abnormalities. In clinical trials, elevation of aminotransferases was observed in patients following ZOLGENSMA infusion [see WARNINGS AND PRECAUTIONS].

Overdose Information for Zolgensma

No Information Provided

Contraindications for Zolgensma

None.

Clinical Pharmacology for Zolgensma

Mechanism Of Action

Onasemnogene abeparvovec is a recombinant AAV9-based gene therapy designed to deliver a copy of the gene encoding the human SMN protein. SMA is caused by a bi-allelic mutation in the SMN1 gene, which results in insufficient SMN protein expression. Intravenous administration of ZOLGENSMA that results in cell transduction and expression of the SMN protein has been observed in two human case studies [see Pharmacokinetics].

Pharmacodynamics

There are no clinically relevant pharmacodynamics data for onasemnogene abeparvovec.

Pharmacokinetics

Vector shedding after infusion with onasemnogene abeparvovec was investigated at multiple time points during Study 2. Samples of saliva, urine and stool were collected the day after infusion, weekly through Day 30, and then monthly through Month 12 and every 3 months thereafter. Samples from 5 patients were used for onasemnogene abeparvovec vector DNA shedding analysis through the Month 18 visit.

Vector DNA was shed in saliva, urine and stool after infusion of onasemnogene abeparvovec, with much higher concentrations of vector DNA found in stool than in saliva or urine. The vector DNA concentration in saliva was low on Day 1 after infusion and declined to undetectable levels within 3 weeks. In urine, the vector DNA concentration was very low on Day 1 after infusion and declined to undetectable levels within 1 to 2 weeks. In stool, the vector DNA concentration was much higher than in saliva or urine for 1 to 2 weeks after infusion and declined to undetectable levels by 1 to 2 months after infusion.

Biodistribution was evaluated in two patients who died 5.7 months and 1.7 months, respectively, after infusion of onasemnogene abeparvovec at the dose of 1.1 x 1014 vg/kg. Both cases showed that the highest levels of vector DNA were found in the liver. Vector DNA was also detected in the spleen, heart, pancreas, inguinal lymph node, skeletal muscles, peripheral nerves, kidney, lung, intestines, gonads, spinal cord, brain, and thymus. Immunostaining for SMN protein showed generalized SMN expression in spinal motor neurons, neuronal and glial cells of the brain, and in the heart, liver, skeletal muscles, and other tissues evaluated.

Animal Toxicology And/Or Pharmacology

In toxicology studies conducted in neonatal mice, dose-dependent cardiac and hepatic toxicities were observed following intravenous administration of onasemnogene abeparvovec. Onasemnogene abeparvovec-related findings in the myocardium, at doses of 7.9 × 1013 vg/kg and higher, included slight to mild mononuclear cell inflammation accompanied by edema, slight to mild fibrosis, and scattered myocardial cell degeneration/regeneration. Additional cardiac findings at dose levels of 1.5 × 1014 vg/kg and higher included minimal to moderate atrial thrombosis and slight to marked atrial dilation. Liver findings included hepatocellular hypertrophy, Kupffer cell activation, perinuclear vacuolation, and scattered hepatocellular necrosis. Target organ toxicity in the heart and liver was associated with mortality in mice at dose levels of 2.4 × 1014 vg/kg and above, approximately 2.2-fold higher than the recommended clinical dose level.

In a 6-month toxicology study conducted in juvenile non-human primates, single intravenous administration of onasemnogene abeparvovec at the recommended clinical dose level of 1.1 × 1014 vg/kg, with or without corticosteroid treatment, resulted in microscopic findings in the dorsal root ganglia (DRG), trigeminal ganglia (TG), spinal cord, brainstem, and liver. At 6 weeks post-administration, microscopic findings included minimal to slight mononuclear cell inflammation and neuronal degeneration in the DRG and TG; axonal degeneration and gliosis in the spinal cord; mixed cell inflammation, gliosis, and axonal degeneration in the brainstem; and oval cell hyperplasia in the liver. These microscopic findings were still present at 6 months with decreased severity and incidence.

Clinical Studies

The efficacy of ZOLGENSMA in pediatric patients less than 2 years of age with SMA with bi-allelic mutations in the SMN1 gene was evaluated in an open-label, single-arm clinical trial (Study 1, NCT03306277) and an open-label, single-arm, ascending-dose clinical trial (Study 2, NCT02122952). Patients experienced onset of clinical symptoms consistent with SMA before 6 months of age. All patients had genetically confirmed bi-allelic SMN1 gene deletions, 2 copies of the SMN2 gene, and absence of the c.859G>C modification in exon 7 of SMN2 gene (which predicts a milder phenotype). All patients had baseline anti-AAV9 antibody titers of ≤ 1:50, measured by ELISA. In both trials, ZOLGENSMA was delivered as a single-dose intravenous infusion.

Efficacy was established on the basis of survival, and achievement of developmental motor milestones, such as sitting without support. Survival was defined as time from birth to either death or permanent ventilation. Permanent ventilation was defined as requiring invasive ventilation (tracheostomy), or respiratory assistance for 16 or more hours per day (including noninvasive ventilatory support) continuously for 14 or more days in the absence of an acute reversible illness, excluding perioperative ventilation. Efficacy was also supported by assessments of ventilator use, nutritional support and scores on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND). CHOP-INTEND is an assessment of motor skills in patients with infantile-onset SMA.

Study 1 enrolled 21 patients (10 male and 11 female) with infantile-onset SMA. Before treatment with ZOLGENSMA, none of the 21 patients required noninvasive ventilator (NIV) support, and all patients could exclusively feed orally (i.e., no need for non-oral nutrition). The mean CHOP-INTEND score at baseline was 31.0 (range, 18 to 47). All the patients received 1.1 × 1014 vg/kg of ZOLGENSMA. The mean age of the 21 patients at the time of treatment was 3.9 months (range, 0.5 to 5.9 months).

As of the March 2019 data cutoff, 19 patients were alive without permanent ventilation (i.e., event-free survival) and were continuing in the trial, while one patient died at age 7.8 months due to disease progression, and one patient withdrew from the study at age 11.9 months. The 19 surviving patients who were continuing in the trial ranged in age from 9.4 to 18.5 months. By the data cutoff, 13 of the 19 patients continuing in the trial reached 14 months of age without permanent ventilation, one of the study’s co-primary efficacy endpoints. In addition to survival, assessment of the other co-primary efficacy endpoint found that 10 of the 21 patients (47.6%) achieved the ability to sit without support for ≥ 30 seconds between 9.2 and 16.9 months of age (mean age was 12.1 months). Based on the natural history of the disease, patients who met the study entry criteria would not be expected to attain the ability to sit without support, and only approximately 25% of these patients would be expected to survive (i.e., being alive without permanent ventilation) beyond 14 months of age. In addition, 16 of the 19 patients had not required daily NIV use.

Comparison of the results of Study 1 to available natural history data of patients with infantile-onset SMA provides primary evidence of the effectiveness of ZOLGENSMA.

Study 2 enrolled 15 patients (6 male and 9 female) with infantile-onset SMA, 3 in a low-dose cohort and 12 in a high-dose cohort. At the time of treatment, the mean age of patients in the low-dose cohort was 6.3 months (range, 5.9 to 7.2 months), and 3.4 months (range, 0.9 to 7.9 months) in the high-dose cohort. The dosage received by patients in the low-dose cohort was approximately one-third of the dosage received by patients in the high-dose cohort. However, the precise dosages of ZOLGENSMA received by patients are unclear due to a change in the method of measuring ZOLGENSMA concentration, and to decreases in the concentration of stored ZOLGENSMA over time. The retrospectively-estimated dosage range in the high-dose cohort is approximately 1.1 × 1014 to 1.4 × 1014 vg/kg.

By 24 months following ZOLGENSMA infusion, one patient in the low-dose cohort met the endpoint of permanent ventilation; all 12 patients in the high-dose cohort were alive without permanent ventilation. None of the patients in the low-dose cohort were able to sit without support, or to stand or walk; in the high-dose cohort, 9 of the 12 patients (75.0%) were able to sit without support for ≥ 30 seconds, and 2 patients (16.7%) were able to stand and walk without assistance. Comparison of the results of the low-dose cohort to the results of the high-dose cohort shows a dose-response relationship that supports the effectiveness of ZOLGENSMA.

Patient Information for Zolgensma

Acute Serious Liver Injury, Acute Liver Failure Or Elevated Aminotransferases

Inform caregivers that ZOLGENSMA could increase liver enzyme levels and cause acute serious liver injury or acute liver failure, and death. Inform caregivers that patients will receive an oral corticosteroid medication before and after infusion with ZOLGENSMA, and will undergo regular blood tests to monitor liver function. Advise caregivers to contact their healthcare provider immediately if the patient’s skin and/or whites of the eyes appear yellowish, if the patient misses a dose of corticosteroid or vomits it up, or if the patient experiences a decrease in alertness [see WARNINGS AND PRECAUTIONS].

Vaccination Before And After Infusion With ZOLGENSMA

Advise caregivers to consult with their healthcare provider to determine if adjustments to the patient’s vaccination schedule are necessary during corticosteroid use. Inform caregivers that where feasible, the vaccination schedule should be adjusted appropriately to accommodate treatment with corticosteroid. Prophylaxis against influenza and RSV is recommended and vaccination status should be up-to-date prior to ZOLGENSMA administration. Please consult your healthcare provider [see DRUG INTERACTIONS].

Systemic Immune Response

Caregivers should be aware that an infection (e.g., cold, flu, gastroenteritis, otitis media, bronchiolitis, etc.) before or after ZOLGENSMA infusion could lead to more serious complications. Caregivers and close contacts of patients should follow infection prevention practices (e.g., hand hygiene, coughing/sneezing etiquette, limiting potential contacts). Advise caregivers of the signs of a possible infection, such as coughing, wheezing, sneezing, runny nose, sore throat, or fever. Caregivers should contact their healthcare provider immediately if the patient experiences any symptoms suggestive of infection before or after ZOLGENSMA infusion [see WARNINGS AND PRECAUTIONS].

Thrombocytopenia

Inform caregivers that ZOLGENSMA could decrease blood platelet count and increase the risk of bruising or bleeding. Inform caregivers that thrombocytopenia has been reported to generally occur within the first two weeks after ZOLGENSMA infusion. Advise caregivers to seek medical attention if the patient experiences unexpected bruising or bleeding [see WARNINGS AND PRECAUTIONS].

Thrombotic Microangiopathy

Inform caregivers that ZOLGENSMA could decrease blood platelet and red blood cell counts, cause acute kidney injury, and increase the risk of bruising or bleeding, which may be indicative of TMA. Inform caregivers that TMA has been reported to generally occur within the first two weeks after ZOLGENSMA infusion. Advise caregivers to seek immediate medical attention if the patient experiences unexpected bruising or bleeding, seizures, or decreased urine output [see WARNINGS AND PRECAUTIONS].

AAV Vector Integration And Risk Of Tumorigenicity

Inform caregivers that there is a theoretical risk of tumorigenicity with AAV therapies such as ZOLGENSMA. Advise caregivers to contact their healthcare provider and Novartis Gene Therapies, Inc. (1-833-828-3947) if the patient who received ZOLGENSMA develops a tumor [see WARNINGS AND PRECAUTIONS].

Vector Shedding

Temporary vector shedding of ZOLGENSMA occurs primarily through body waste. Advise caregivers on the proper handling of patient feces; recommended procedures include sealing disposable diapers in disposable trash bags and then discarding into regular trash. Provide instructions to caregivers and family members regarding proper hand hygiene when coming into direct contact with patient body waste. These precautions should be followed for one month after ZOLGENSMA infusion.

Infusion-Related Reactions

Inform caregivers that infusion-related reactions may occur during and after ZOLGENSMA infusion. Advise caregivers to seek immediate medical evaluation if signs and symptoms of infusion related reaction occur which may include rash, urticaria, vomiting, dyspnea, respiratory symptoms and/or alterations in heart rate and blood pressure [see WARNINGS AND PRECAUTIONS].