Brand name: Zolgensma
Drug class: Gene Therapy

Introduction

Onasemnogene abeparvovec-xioi is a recombinant adeno-associated virus serotype 9 (AAV9) vector-based gene therapy containing a transgene encoding the human survival motor neuron (SMN) protein.

Uses for Onasemnogene Abeparvovec-xioi

Onasemnogene abeparvovec has the following uses:

Onasemnogene abeparvovec-xioi is 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. Designated an orphan drug by FDA for the treatment of spinal muscular atrophy.

SMA is an autosomal recessive disorder that is mainly caused by a homozygous mutation in the SMN1 gene, which leads to SMN protein deficiency. A single IV infusion of onasemnogene abeparvovec delivers a copy of the SMN1 gene into target motor neurons, increasing production of SMN protein; such therapy has been shown to improve motor function and prolong survival without permanent assisted ventilation in children younger than 2 years of age with SMA.

Efficacy of onasemnogene abeparvovec was evaluated in an ongoing open-label, single-arm trial and a completed open-label, single-arm, ascending-dose trial in patients with genetically confirmed bi-allelic mutations in the SMN1 gene. 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. Evidence of efficacy was principally established based on a comparison of the results of the ongoing trial with data from a natural history cohort of patients with infantile-onset SMA. At the time of data analysis, 19 out of 21 patients were alive without permanent ventilation and were continuing in the trial; in addition, 10 out of the 21 patients achieved the ability to sit without support for more than 30 seconds between 9.2 and 16.9 months of age. 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. Results of the completed study demonstrated a dose-response relationship that support the effectiveness of onasemnogene abeparvovec.

The safety and effectiveness of repeat administration of onasemnogene abeparvovec have not been evaluated.

The use of onasemnogene abeparvovec in patients with advanced SMA (e.g., complete paralysis of limbs, permanent ventilator dependence) has not been evaluated.

Onasemnogene Abeparvovec-xioi Dosage and Administration

General

Onasemnogene abeparvovec-xioi is available in the following dosage form(s) and strength(s):

Suspension for IV infusion, supplied as single-use vials.

Onasemnogene abeparvovec-xioi 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 × 10¹³ vector genomes (vg) per mL. Each vial of onasemnogene abeparvovec contains an extractable volume of not less than either 5.5 mL or 8.3 mL.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Pediatric Patients

Dosage and Administration

Onasemnogene abeparvovec-xioi is for single-dose IV infusion only.

• The recommended dose of onasemnogene abeparvovec-xioi in pediatric patients younger than 2 years of age with spinal muscular atrophy (SMA) is 1.1 × 10¹⁴ vector genomes (vg) per kg of body weight. Administration of onasemnogene abeparvovec-xioi to premature neonates before reaching full-term gestational age is not recommended.

• Administer onasemnogene abeparvovec as an IV infusion over 60 minutes. DO NOT INFUSE AS AN IV PUSH OR BOLUS. Flush line with saline following completion of infusion.

• Postpone onasemnogene abeparvovec 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 onasemnogene abeparvovec infusion.

• Starting one day prior to onasemnogene abeparvovec infusion, 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 of systemic corticosteroid treatment, 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.

• If liver function abnormalities continue to persist ≥ 2 × ULN after the 30-day period of systemic corticosteroids, promptly consult a pediatric gastroenterologist or hepatologist.

• See Full Prescribing Information for additional instructions on preparation and administration.

Cautions for Onasemnogene Abeparvovec-xioi

Contraindications

None.

Warnings/Precautions

Acute Serious Liver Injury, Acute Liver Failure or Elevated Aminotransferases

Acute serious liver injury, acute liver failure and elevated aminotransferases can occur with onasemnogene abeparvovec. 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 onasemnogene abeparvovec-xioi use. In order to mitigate potential aminotransferase elevations, administer systemic corticosteroid to all patients before and after onasemnogene abeparvovec infusion. Immune-mediated hepatotoxicity may require adjustment of the corticosteroid treatment regimen, including longer duration, increased dose, or prolongation of the corticosteroid taper.

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 onasemnogene abeparvovec. Carefully consider the risks and benefits of onasemnogene abeparvovec therapy in patients with preexisting liver impairment.

Although in the clinical trials and in postmarketing experience, asymptomatic aminotransferase elevations were very commonly reported, 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 onasemnogene abeparvovec 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 onasemnogene abeparvovec 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 onasemnogene abeparvovec 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.

Systemic Immune Response

Due to activation of humoral and cellular immunity following onasemnogene abeparvovec 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). Patients with infection were excluded from participation in onasemnogene abeparvovec clinical trials. Recommend increased vigilance in the prevention, monitoring, and management of infection before and after onasemnogene abeparvovec infusion.

To mitigate the risk of serious and life-threatening systemic immune response, administer onasemnogene abeparvovec 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 onasemnogene abeparvovec 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 onasemnogene abeparvovec infusion. Recommend seasonal prophylaxis against influenza and respiratory syncytial virus (RSV) and vaccination status should be up-to-date prior to onasemnogene abeparvovec administration.

Thrombocytopenia

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

Monitor platelet counts before onasemnogene abeparvovec 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).

Thrombotic Microangiopathy

Cases of thrombotic microangiopathy (TMA) were reported to occur generally within the first two weeks after onasemnogene abeparvovec-xioi infusion in the post-marketing setting. 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, 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) were observed following onasemnogene abeparvovec-xioi infusion in clinical trials. The clinical importance of these findings is not known. However, cardiac toxicity was observed in animal studies. Monitor troponin-I before onasemnogene abeparvovec infusion and on a regular basis for at least 3 months afterwards (weekly for the first month, and then monthly for the second and third months until troponin-I level returns to baseline). Consider consultation with a cardiologist, if troponin elevations are accompanied by clinical signs or symptoms (e.g., heart rate changes, cyanosis, tachypnea and respiratory distress).

Specific Populations

Pregnancy

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

In the U.S. 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

There is no information available on the presence of onasemnogene abeparvovec 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 onasemnogene abeparvovec and any potential adverse effects on the breastfed child from onasemnogene abeparvovec or from the underlying maternal condition.

Pediatric Use

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

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

The safety of onasemnogene abeparvovec-xioi was studied in pediatric patients who received onasemnogene abeparvovec infusion at age 0.3 to 7.9 months (weight range, 3.0 kg to 8.4 kg).

The efficacy of onasemnogene abeparvovec-xioi was studied in pediatric patients who received onasemnogene abeparvovec infusion at age 0.5 to 7.9 months (weight range, 3.6 kg to 8.4 kg).

Hepatic Impairment

Onasemnogene abeparvovec therapy should be carefully considered in patients with liver impairment. Cases of acute serious liver injury and acute liver failure have been reported with onasemnogene abeparvovec-xioi in patients with preexisting liver abnormalities. In clinical trials, elevation of aminotransferases was observed in patients following onasemnogene abeparvovec infusion.

Common Adverse Effects

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

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Where feasible, adjust a patient’s vaccination schedule to accommodate concomitant corticosteroid administration prior to and following onasemnogene abeparvovec infusion.

Actions

Mechanism of Action

Onasemnogene abeparvovec is a recombinant adeno-associated virus serotype 9 (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. IV administration of onasemnogene abeparvovec that results in cell transduction and expression of the SMN protein has been observed in two human case studies.

Advice to Patients

• Inform caregivers that onasemnogene abeparvovec 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 onasemnogene abeparvovec, 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.

• 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 onasemnogene abeparvovec administration.

• Caregivers should be aware that an infection (e.g., cold, flu, gastroenteritis, otitis media, bronchiolitis) before or after onasemnogene abeparvovec 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 onasemnogene abeparvovec infusion.

• Inform caregivers that onasemnogene abeparvovec 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 onasemnogene abeparvovec infusion. Advise caregivers to seek medical attention if the patient experiences unexpected bruising or bleeding.

• Inform caregivers that onasemnogene abeparvovec 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 thrombotic microangiopathy (TMA). Inform caregivers that TMA has been reported to generally occur within the first two weeks after onasemnogene abeparvovec infusion. Advise caregivers to seek immediate medical attention if the patient experiences unexpected bruising or bleeding, seizures, or decreased urine output.

• Temporary vector shedding of onasemnogene abeparvovec 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 onasemnogene abeparvovec infusion.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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Frequently asked questions

• Is Zolgensma a cure for SMA?

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