Onasemnogene Abeparvovec

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 ( 6.2 )] . 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 ( 14 )] . 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. ( 1 ) Limitations of Use The safety and effectiveness of repeat administration of ZOLGENSMA have not been evaluated. ( 1 , 6.2 ) The use of ZOLGENSMA in patients with advanced SMA (e.g., complete paralysis of limbs, permanent ventilator dependence) has not been evaluated. ( 1 , 14 )

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 × 10 13 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 × 10 14 vg/kg for pediatric patients. ZOLGENSMA is a suspension for intravenous infusion, supplied as single-use vials. ( 3 ) ZOLGENSMA is provided in a kit containing 2 to 14 vials, as a combination of 2 vial fill volumes (either 5.5 mL or 8.3 mL). All vials have a nominal concentration of 2.0 × 10 13 vector genomes (vg) per mL. Each vial of ZOLGENSMA contains an extractable volume of not less than either 5.5 mL or 8.3 mL. ( 3 )

None. None. ( 4 )

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. ( 5.2 ) Thrombocytopenia: Monitor platelet counts before ZOLGENSMA infusion, and at least weekly for the first month and then every other week for the second and third month or until platelet counts return to baseline. ( 2.3 , 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 pediatric hematologist and/or pediatric nephrologist immediately to manage as clinically indicated. ( 5.4 ) Elevated Troponin I: Increases in cardiac troponin I levels have occurred following ZOLGENSMA infusion. Consider cardiac evaluation after ZOLGENSMA infusion 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 ZOLGENSMA, to Novartis Gene Therapies, Inc. ( 5.6 , 17 ) Infusion-Related Reactions: Monitor patients during and after ZOLGENSMA infusion. Interrupt ZOLGENSMA infusion if infusion-related reaction occurs and administer supportive treatment as appropriate. Infusion of ZOLGENSMA may be resumed based on clinical assessment. ( 5.7 )

5.1 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 ( 6 )] . 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 ( 2.1 )] . 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 ( 6.1 )] , 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 ( 2.3 )] .

5.2 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 ( 2.1 )] . Recommend seasonal prophylaxis against influenza and respiratory syncytial virus (RSV) and vaccination status should be up-to-date prior to ZOLGENSMA administration.

5.3 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 (2.3) ].

5.4 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 ( 6.3 )] . 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 Warnings and Precautions ( 5.3 )] , 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.

5.5 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 ( 13.2 )] . Consider cardiac evaluation after ZOLGENSMA infusion and consult a cardiologist as needed. […]

The most common adverse reactions (incidence ≥ 5%) were elevated aminotransferases and vomiting. The most common adverse reactions (incidence ≥ 5%) were elevated aminotransferases and vomiting. ( 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 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 ( 14 )] . 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 ( 5.1 )] . 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 ( 5.3 )] . 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 (%) Abbreviations: ULN, upper limit of normal; ALT, alanine aminotransferase. *Laboratory finding. Elevated aminotransferases 12 (27%) ALT > 3 X ULN 7 (16%) ALT > 20 X ULN 4 (9%) Vomiting 3 (7%) 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.

6.2 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 ( 5.4 )] , thrombocytopenia [see Warnings and Precautions ( 5.3 )] Hepatobiliary Disorders : acute liver failure (fatal and non-fatal), acute liver injury [see Warnings and Precautions ( 5.1 )] General Disorders and Administration Site Conditions : pyrexia, infusion-related reactions [see Warnings and Precautions ( 5.7 )] Investigations : troponin increased [see Warnings and Precautions ( 5.5 )]

Where feasible, adjust a patient’s vaccination schedule to accommodate concomitant corticosteroid administration prior to and following ZOLGENSMA infusion [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). 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). Where feasible, adjust a patient’s vaccination schedule to accommodate concomitant corticosteroid administration prior to and following ZOLGENSMA infusion. ( 7 )

Pediatric Use: Use of ZOLGENSMA in 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 full-term gestational age is reached. ( 8.4 )

8.1 Pregnancy Risk Summary There are no available data regarding ZOLGENSMA use in pregnant women. It is not known whether ZOLGENSMA has the potential to be transferred to the fetus in humans. Animal reproduction studies in mice have shown no risk of fetal abnormalities nor transfer to mouse fetus with intravenous (IV) administration of onasemnogene abeparvovec, the active ingredient found in ZOLGENSMA, on gestational day 6 at dose levels equivalent to the clinical IV dose of ZOLGENSMA [see Carcinogenesis, Mutagenesis, Impairment of Fertility ( 13.1 )] , see Animal Data. 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. Data Animal Data In an embryo-fetal development study in mice, pregnant animals received an IV dose of either 1.1 x 10 13 vg/kg or 1.1 x 10 14 vg/kg of onasemnogene abeparvovec on gestational day 6, which resulted in no evidence of maternal toxicity, embryo-fetal toxicity, teratogenicity, or reduced viability. Onasemnogene abeparvovec DNA was detected in the placenta at low levels but was not detected in any fetal tissue at gestational day 18. The no observed adverse effect level for maternal and developmental toxicity is 1.1 x 10 14 vg/kg, which is the recommended clinical IV dose of ZOLGENSMA.

8.2 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.

8.4 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 ( 6 )] . 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 ( 14 )] . 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.

8.6 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 ( 5.1 )] .

ZOLGENSMA 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 Clinical Pharmacology ( 12.3 )] .