Onasemnogene abeparvovec is an adeno-associated virus vector gene therapy indicated for the treatment of pediatric patients younger than 2 years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene. SMA is a rare and often fatal hereditary genetic disease affecting muscle strength and movement. It causes weakness and muscle wasting because of the loss of lower motor neurons controlling movement. The age of onset, symptoms, and rate of progression vary widely between patients. Onasemnogene abeparvovec is given as a single dose and carries a boxed warning for acute serious liver injury and acute liver failure. The most common adverse reactions of onasemnogene abeparvovec are elevated liver enzymes and vomiting. An ongoing clinical trial and a completed trial in 36 pediatric patients with infantile-onset SMA (between the ages of approximately 2 weeks and 8 months at study entry) assessed the percentage of patients who survived and achieved developmental motor milestones such as sitting without support. Efficacy was also supported by assessment of ventilator use, nutritional support, and scores on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND), a test assessing motor skills in patients with infantile-onset SMA. Efficacy was based on the ongoing clinical trial; the completed clinical trial determined the dose-response relationship that helped support the effectiveness of onasemnogene abeparvovec. In a planned interim efficacy analysis including 21 patients, 19 patients (9.4 to 18.5 months of age) were alive without permanent ventilation; 13 of these patients reached 14 months of age without permanent ventilation. Additionally, 47.6% of patients were able to sit without support for at least 30 seconds. Based on the natural history of the disease, none of the patients that met the study entry criteria would have been expected to sit without support and only approximately 25% of these patients would be expected to survive beyond 14 months. Because thrombocytopenia, hepatic injury, and potential cardiac toxicity can occur after onasemnogene abeparvovec infusion, platelet count, liver function (by clinical examination and laboratory testing), and cardiac troponin-I concentrations are recommended at baseline and on a regular basis for at least 3 months after therapy.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Preparation
-Thaw onasemnogene abeparvovec before use. The onasemnogene abeparvovec 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 on day of dosing.
-Onasemnogene abeparvovec is a clear to slightly opaque, colorless to faint white liquid. Do not administer if visible particulates are observed or if the liquid in the vial is discolored.
-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.
-Administer onasemnogene abeparvovec within 8 hours of drawing into syringe.
-Storage: Discard the vector-containing syringe if the drug is not infused within the 8-hour timeframe. Do not refreeze.
IV Infusion-Place primary catheter into a vein (generally a peripheral vein in the arm or leg). Insertion of back-up catheter is recommended.
-Program syringe pump for saline priming, or prime tubing manually with saline.
-Administer onasemnogene abeparvovec as a slow infusion over 60 minutes. Do NOT infuse as an intravenous push or bolus.
During onasemnogene abeparvovec clinical trials, patients were required to have baseline anti-AAV9 antibody titers of 1:50 or less, measured using an enzyme-linked immunosorbent assay (ELISA). Evidence of prior exposure to AAV9 was uncommon. The safety and efficacy of onasemnogene abeparvovec 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 onasemnogene abeparvovec infusion. Retesting may be performed if anti-AAV9 antibody titers more than 1:50 are reported. Increases from baseline in anti-AAV9 antibody titers occurred in all patients after onasemnogene abeparvovec infusion. In the completed clinical trial, 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 onasemnogene abeparvovec in the presence of high anti-AAV9 antibody titers has not been evaluated.
During clinical trials, onasemnogene abeparvovec use was associated with transient decreases in platelet counts, some of which met the criteria for thrombocytopenia. The decreased platelets occurred at different time points after onasemnogene abeparvovec infusion. Thrombotic microangiopathy (TMA), characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury, has been reported in patients who received onasemnogene abeparvovec during the postmarketing period generally within the first 2 weeks. Concurrent immune system activation (e.g., infections, vaccinations) was identified in some cases. Transient increases in cardiac troponin-I concentrations (up to 0.176 mcg/L) were observed after onasemnogene abeparvovec infusion in clinical trials. The clinical importance of these findings is unknown; however, cardiac toxicity was observed in animal studies.
Hepatotoxicity and aminotransferase elevations have been reported with the use of onasemnogene abeparvovec. During clinical trials, elevated hepatic enzymes (alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST)) were reported in 12 of the 44 patients (27.3%). Although hepatotoxicity usually manifests as elevated ALT and/or AST enzymes, acute serious liver injury or acute hepatic failure, including death, has been reported during postmarketing experience. Some patients have experienced elevations in ALT and AST more than 20 times the upper limit of normal (ULN), prolonged prothrombin time, and have been symptomatic (e.g., vomiting, jaundice). Corticosteroid therapy has been required with some patients requiring a prolonged duration and/or a higher dose. Administer systemic corticosteroids before and after onasemnogene abeparvovec infusion. Adjustment of the corticosteroid treatment regimen, including longer duration, increased dose, or prolongation of the corticosteroid taper may be necessary for immune-mediated hepatotoxicity. Liver function monitoring at baseline and weekly for the first month after infusion and during the corticosteroid taper period (28 days or longer if needed) is recommended. For patients that are clinically stable with unremarkable findings at the end of the corticosteroid taper period, continue to monitor liver function every other week for another month. If acute serious hepatotoxicity or acute hepatic failure is suspected, consult a pediatric gastroenterologist or hepatologist.
During clinical trials of onasemnogene abeparvovec, vomiting was reported in 3 of the 44 patients (6.8%).
Pyrexia (fever) was reported during postmarketing experience. One patient in a clinical trial initially presented with respiratory insufficiency 12 days after onasemnogene abeparvovec infusion. The patient was found to have respiratory syncytial virus (RSV) infection and parainfluenza. The patient had episodes of serious hypotension, followed by seizures, and leukoencephalopathy (brain white matter defects) was discovered approximately 30 days after onasemnogene abeparvovec infusion. The patient died after withdrawal of life support 52 days after onasemnogene abeparvovec infusion.
There is a theoretical risk of tumorigenicity due to integration of the AAV vector DNA into the genome. Cases of tumor have been reported in patients during postmarketing use of onasemnogene abeparvovec; however, information on the cases is limited and a causal relationship has not been established. If a tumor develops in a patient receiving onasemnogene abeparvovec, report the tumor to the manufacturer. Onasemnogene abeparvovec 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 in the literature with other AAV gene therapies. The clinical relevance of integration events is unknown, but it is acknowledged that integration could potentially contribute to a risk of tumorigenicity.
Use onasemnogene abeparvovec with caution in patients with thrombocytopenia; onasemnogene abeparvovec use has been associated with transient decreases in platelet counts, especially within the first 2 weeks after infusion. Monitor platelets before onasemnogene abeparvovec infusion and closely monitor platelet counts within the first 2 weeks after infusion and on a regular basis afterwards (at least weekly for the first month, then every other week for the second and third months until platelet counts return to baseline).
Use onasemnogene abeparvovec with caution in patients with cardiac disease. Transient increases in cardiac troponin-I concentrations (up to 0.176 mcg/L) were observed after onasemnogene abeparvovec infusion in clinical trials. The clinical importance of these findings is unknown; however, cardiac toxicity was observed in animal studies. Monitor troponin-I concentrations before onasemnogene abeparvovec infusion and on a regular basis afterwards (weekly for the first month then monthly for the second and third months until concentrations return to baseline). Consider cardiologist consultation if troponin elevations are accompanied by clinical signs or symptoms (e.g., heart rate changes, cyanosis, tachypnea, and respiratory distress).
The risk of serious systemic immune response is increased in patients with a concurrent infection receiving onasemnogene abeparvovec, potentially resulting in more severe clinical courses of the infection. Due to activation of humoral and cellular immunity after onasemnogene abeparvovec infusion, patients with an active infection, either acute (e.g., respiratory, gastrointestinal) or chronic uncontrolled (e.g., chronic active hepatitis B) may be at an increased risk. Patients may present with high fever, hypotension, etc. To decrease the risk of serious and life-threatening systemic immune response, administer onasemnogene abeparvovec to patients who are clinically stable in their baseline health (e.g., hydration and nutritional status, absence of infection) prior to infusion. Postpone onasemnogene abeparvovec in patients with concurrent 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 administration. Closely monitor patients to prevent, manage, and monitor for infection. Ensure that recommended seasonal prophylaxis against influenza and respiratory syncytial virus (RSV) and vaccination status are up to date prior to administration.
Hepatotoxicity, aminotransferase elevations, and acute liver failure, including fatal cases, have been reported with the use of onasemnogene abeparvovec. Patients with pre-existing hepatic disease or acute hepatic viral infection may be at a higher risk of developing acute serious liver injury. Patients with alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin concentrations, excluding neonatal jaundice, more than 2 times the upper limit of normal (ULN) have not been studied in onasemnogene abeparvovec clinical trials. Use caution when administering onasemnogene abeparvovec to any patient with known hepatic disease. Weigh the risks and benefits of drug administration in patients with pre-existing hepatic impairment carefully against the risks of not treating the patient. Prior to onasemnogene abeparvovec infusion, assess liver function by clinical examination and laboratory testing (e.g., AST, ALT, total bilirubin, albumin, prothrombin time, partial thromboplastin time [PTT], and international normalized ratio [INR]). Administer systemic corticosteroids before and after onasemnogene abeparvovec infusion. Adjustment of the corticosteroid treatment regimen, including longer duration, increased dose, or prolongation of the corticosteroid taper may be necessary for immune-mediated hepatotoxicity. Monitor liver function (AST, ALT, total bilirubin, prothrombin time, INR) weekly for the first month after infusion and during the corticosteroid taper period (28 days or longer if needed). For patients that are clinically stable with unremarkable findings at the end of the corticosteroid taper period, continue to monitor liver function every other week for another month. If acute serious hepatotoxicity or acute liver failure is suspected, consult a pediatric gastroenterologist or hepatologist. Closely monitor patients with worsening liver function tests and/or signs or symptoms of acute illness (e.g., vomiting, deterioration in health). If hepatic injury is suspected, further testing of albumin, PTT, and INR is recommended.
There are no available data regarding the use of onasemnogene abeparvovec during pregnancy to inform a drug-associated risk. Clinical studies in women or in animals during pregnancy are not available.
There are no data on the presence of onasemnogene abeparvovec in human milk, the effects on a breast-fed infant, or the effects on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Onasemnogene abeparvovec infusion is given in conjunction with oral corticosteroids. When feasible, adjust a patient's vaccination schedule to accommodate concomitant corticosteroid administration prior to and after onasemnogene abeparvovec infusion. Seasonal RSV prophylaxis is not precluded. Corticosteroid therapy usually does not contraindicate vaccination with live-virus vaccines when such therapy is of short-term (less than 2 weeks); low to moderate dose; long-term alternate day treatment with short-acting preparations; maintenance physiologic doses (replacement therapy); or administration topically (skin or eye), by aerosol, or by intra-articular, bursal, or tendon injection. The immunosuppressive effects of steroid treatment differ, but many clinicians consider a dose equivalent to either 2 mg/kg/day or 20 mg/day of prednisone as sufficiently immunosuppressive to raise concern about the safety of immunization with live-virus vaccines. In general, patients with severe immunosuppression due to large doses of corticosteroids should not receive vaccination with live-virus vaccines (e.g., MMR and varicella). Patients vaccinated while on immunosuppressive therapy or in the 2 weeks prior to starting therapy should be considered unimmunized and should be revaccinated at least 3 months after discontinuation of therapy. In patients who have received high-dose, systemic corticosteroids for 2 weeks or more, it is recommended to wait at least 1 month after discontinuation of therapy before administering a live-virus vaccine.
Thrombotic microangiopathy (TMA) has been reported in patients who received onasemnogene abeparvovec, generally within the first 2 weeks after infusion. TMA can be life-threatening or fatal; close monitoring for signs and symptoms of TMA is recommended. Monitor platelet counts closely within the first 2 weeks after infusion and on a regular basis afterwards. Monitor for signs and symptoms of TMA, which include hypertension, increased bruising, seizures, or decreased urine output. If these signs and symptoms occur in addition to thrombocytopenia, further evaluate for hemolytic anemia and renal dysfunction. If clinical signs, symptoms, and/or laboratory findings are present, consult with a pediatric hematologist and/or pediatric nephrologist immediately to manage TMA as clinically indicated. Thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury may occur with TMA. Concurrent immune system activation (e.g., infections, vaccinations) was identified in some cases.
There is a theoretical risk of tumorigenicity due to integration of the AAV vector DNA into the genome. Onasemnogene abeparvovec 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 in the literature with other AAV gene therapies. The clinical relevance of integration events is unknown, but it is acknowledged that integration could potentially contribute to a risk of tumorigenicity. If a tumor develops in a patient receiving onasemnogene abeparvovec, report the tumor to the manufacturer.
For the treatment of spinal muscular atrophy (SMA):
NOTE: The FDA has designated onasemnogene abeparvovec as an orphan drug for this indication.
Intravenous dosage:
Infants and Children younger than 2 years of age: 1.1 x 1014 vector genomes (vg)/kg as a single IV dose administered over 60 minutes. Starting 1 day prior to onasemnogene abeparvovec infusion, administer systemic corticosteroids equivalent to oral prednisolone 1 mg/kg/day for a total of 30 days. Monitor liver function on a regular basis, and at other times as clinically indicated. Check liver function, clinically, and by assessing laboratory values (i.e., ALT, AST, total bilirubin, prothrombin time, and INR) at the end of 30 days of corticosteroid treatment. For patients with unremarkable findings, taper the corticosteroid dose over the next 28 days. Do not stop systemic corticosteroids abruptly. If liver function abnormalities persist, continue systemic corticosteroids until findings become unremarkable, and then taper the corticosteroid dose over the next 28 days or longer if needed. Do not stop systemic corticosteroids abruptly. Promptly consult a pediatric gastroenterologist or hepatologist if patients do not respond to steroid therapy. Consider intravenous corticosteroids if oral corticosteroid therapy is not tolerated.
Neonates: 1.1 x 1014 vector genomes (vg)/kg as a single IV dose administered over 60 minutes. Starting 1 day prior to onasemnogene abeparvovec infusion, administer systemic corticosteroids equivalent to oral prednisolone 1 mg/kg/day for a total of 30 days. Monitor liver function on a regular basis, and at other times as clinically indicated. Check liver function, clinically, and by assessing laboratory values (i.e., ALT, AST, total bilirubin, prothrombin time, and INR) at the end of 30 days of corticosteroid treatment. For patients with unremarkable findings, taper the corticosteroid dose over the next 28 days. Do not stop systemic corticosteroids abruptly. If liver function abnormalities persist, continue systemic corticosteroids until findings become unremarkable, and then taper the corticosteroid dose over the next 28 days or longer if needed. Do not stop systemic corticosteroids abruptly. Promptly consult a pediatric gastroenterologist or hepatologist if patients do not respond to steroid therapy. Consider intravenous corticosteroids if oral corticosteroid therapy is not tolerated.
Therapeutic Drug Monitoring:
-Assess baseline anti-AAV9 antibody testing prior to onasemnogene abeparvovec infusion. If anti-AAV9 antibody titers are more than 1:50, retesting may be performed.
-Assess baseline serum creatinine.
-Assess baseline liver function (clinical exam, AST, ALT, total bilirubin, albumin, prothrombin time, PTT, INR) and then weekly liver function (clinical exam, AST, ALT, total bilirubin, prothrombin time, INR) for the first month and during the corticosteroid taper. If results are unremarkable (normal clinical exam, total bilirubin, prothrombin, and INR results, and AST and ALT concentrations below 2 times upper limit of normal) at the end of corticosteroid taper, continue to monitor every other week for another month.
-Assess baseline complete blood count, including hemoglobin and platelet count, and then weekly platelet counts for the first month, and then every other week for the second and third months, until platelet counts return to baseline.
-Assess baseline and then weekly troponin-I for the first month, and then monthly for the second and third months, until troponin-I concentration returns to baseline.
Maximum Dosage Limits:
-Adults
Safety and efficacy have not been established.
-Geriatric
Safety and efficacy have not been established.
-Adolescents
Safety and efficacy have not been established.
-Children
2 to 12 years: Safety and efficacy have not been established.
1 year: 1.1 x 1014 vector genomes (vg)/kg as a single IV dose.
-Infants
1.1 x 1014 vector genomes (vg)/kg as a single IV dose.
-Neonates
Full-term neonates: 1.1 x 1014 vector genomes (vg)/kg as a single IV dose.
Premature neonates: Delay onasemnogene abeparvovec infusion until full-term gestational age is reached.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Although dosage adjustments are not available, monitor liver function before and after onasemnogene abeparvovec therapy because acute serious liver injury and acute liver failure have occurred.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Onasemnogene Abeparvovec products.
Onasemnogene abeparvovec is a recombinant AAV9-based gene therapy designed to deliver a copy of the gene encoding the human survival motor neuron (SMN) protein. Spinal muscular atrophy (SMA) is caused by a bi-allelic mutation in the SMN1 gene, which results in insufficient SMN protein expression. Intravenous administration of onasemnogene abeparvovec resulting in cell transduction and expression of the SMN protein has been observed in 2 human cases.
Onasemnogene abeparvovec is administered intravenously. Vector shedding after onasemnogene abeparvovec infusion was investigated at multiple time points during a clinical trial. Samples of saliva, urine, and stool were collected from 5 patients and were used for onasemnogene abeparvovec vector DNA shedding analysis through the Month 18 visit. Vector DNA was shed in salvia, urine, and stool after onasemnogene abeparvovec infusion, 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. In 2 patients who died 5.7 months and 1.7 months after onasemnogene abeparvovec infusion, biodistribution was evaluated. Both cases showed the highest concentrations of vector DNA in the liver. Vector DNA was also detected in the spleen, heart, pancreas, inguinal lymph node, skeletal muscles, peripheral nerves, kidney, lung, intestines, spinal cord, brain, and thymus. Immunostaining for survival motor neuron (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.