Overview:
Onasemnogene abeparvovec is a drug designed to treat spinal muscular atrophy (SMA), a group of neuromuscular disorders characterized by progressive muscle wasting and the loss of motor neurons. The drug is indicated for use in children under two years of age diagnosed with SMA (spinal muscular atrophy) through genetic testing. While the drug is administered as a one-time infusion over an hour, it is extremely expensive. In fact, it is the most expensive drug ever marketed. SMA can manifest at different ages and with varying levels of severity, resulting in muscle weakness and twitching, particularly in the lower extremities and, in severe cases, the pulmonary and masticatory muscles. SMA is also one of the leading genetic causes of death in children.
Spinal muscular atrophy (SMA) is characterized by a group of neuromuscular disorders that lead to progressive muscle wasting and the loss of motor neurons. The severity of the symptoms depends on the specific type of SMA, with some types being noticeable at or before birth while others only manifest in adulthood. Regardless of the type, all types of SMA generally cause progressive muscle weakness accompanied by muscle twitching. The muscles of the lower extremities are usually the first to be affected, followed by those in the upper extremities, spine, neck, and, in severe cases, pulmonary and mastication muscles. Proximal muscles are typically affected earlier and more severely than distal muscles. SMA is one of the primary genetic causes of death in children.
How Does Onasemnogene Abeparvovec Work?
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Onasemnogene abeparvovec is indicated for the treatment of spinal muscular atrophy (SMA) in infant patients less than two years of age who have a specific mutation in the survival motor neuron 1 (SMN1) gene.
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SMA (spinal muscular atrophy) is a rare genetic disease that causes motor neuron dysfunction and survival, leading to severe and often fatal muscle weakness.
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While Onasemnogene abeparvovec does not offer a cure for SMA, it is a disease-modifying treatment that can slow the progression of the disease, enhance motor function, and manage symptoms.
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The efficacy of the drug in SMA patients, including those who have total limb paralysis and require permanent ventilator assistance, has not been established.
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Another gene therapy, Nusinersen, is also Food and Drug Administration (FDA)-approved for the treatment of SMA in pediatric and adult patients.
Uses:
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Onasemnogene abeparvovec is a medication developed to address spinal muscular atrophy, a condition commonly diagnosed in young children and linked to a mutation in the SMN1 gene on chromosome 5q. This genetic disorder leads to progressive loss of muscle function and often death.
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Onasemnogene abeparvovec is given as an intravenous infusion and has been approved in the United States and other countries for use in children with spinal muscular atrophy under the age of two, including during the presymptomatic stage.
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In the European Union and Canada, it is indicated for the treatment of patients diagnosed with spinal muscular atrophy type 1 or who possess up to three copies of the SMN2 gene. Corticosteroids are administered alongside the medication to help safeguard the liver.
Dosage and Strengths:
Onasemnogene abeparvovec is provided as a suspension for IV infusions and is available in a kit containing 2 to 9 vials. The vials have a nominal concentration of 2 x 10^13 vector genomes (vg) per mL and contain an extractable volume of not less than either 5.5 mL or 8.3 mL. The combination of vial fill volumes (either 5.5 mL or 8.3 mL) varies in each kit.
Warning:
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Acute Serious Liver Injury or Acute Liver Failure - Onasemnogene abeparvovec has been associated with acute serious liver injury, acute liver failure, and elevated liver enzymes. Some cases of acute liver failure have resulted in fatalities. Patients who have pre-existing liver problems may be at higher risk for liver injury. Therefore, it is recommended that, before infusion, a liver function test be done in all patients through clinical examination and laboratory testing, including AST (aspartate transaminase) or ALT (alanine transaminase), total bilirubin, and prothrombin time. Furthermore, all patients should receive systemic corticosteroids before and after infusion. Liver function should continue to be monitored for at least three months after infusion or as deemed necessary by the clinician.
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Systemic Immune Response - Following infusion, activation of humoral and cellular immunity can lead to a systemic immune response in patients. Those with active infections, whether chronic and uncontrolled or acute, such as respiratory or gastrointestinal infections, may have an increased risk of a severe clinical course of the infection due to this immune response. Serious systemic immune responses can present with various symptoms, including high fever and hypotension. To minimize the risk of a potentially life-threatening systemic immune response, patients should be administered the infusion only when they are clinically stable, with their overall baseline health status assessed, including hydration and nutritional status, and the absence of any infections.
Patients with infections should have their infusions postponed until their infections have resolved and they are clinically stable. Infection prevention, monitoring, and management should be increased before and after infusion, and seasonal prophylaxis against influenza, RSV, and COVID-19 is recommended. Patients should also have current vaccination status before administration.
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Thrombocytopenia - There have been reports of a temporary reduction in platelet counts after infusion, with some cases meeting the criteria for thrombocytopenia. Therefore, it is recommended to regularly monitor the patient's platelet counts before the infusion and at specific intervals after the infusion.
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Thrombotic Microangiopathy - Thrombotic microangiopathy (TMA) is a condition that has been reported within the first two weeks after infusion. It is characterized by a combination of thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury. In some cases, concurrent activation of the immune system (such as infections or vaccinations) was identified. Platelet counts must be regularly monitored, along with other symptoms of TMA, such as seizures, hypertension, bruising, and decreased urine output. In case of clinical signs, symptoms, and/or laboratory findings consistent with TMA.
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Elevated Troponin-I - After the infusion, an increase in cardiac troponin-I levels has been observed, but the significance of this is unknown. Animal studies have shown cardiac toxicity. To assess potential cardiac effects, troponin-I levels should be monitored before infusion and for a minimum of three months afterward (weekly for the first month and then every two weeks for the next two months). If there are any clinical signs or symptoms accompanying the troponin elevation, such as changes in heart rate, cyanosis, tachypnea, or respiratory distress, a cardiology consultation should be considered.
For Patients:
Learn About Spinal Muscular Atrophy
What Is Spinal Muscular Atrophy?
SMA is an uncommon genetic disorder that arises from a mutation in the SMN1 gene, which produces the SMN protein essential for maintaining and functioning motor neurons. The loss of functional SMN protein causes motor neurons to perish, resulting in severe and sometimes fatal muscle weakness. The various subtypes of SMA, which are classified according to onset age and severity, are usually caused by mutations in the SMN1 gene, with infantile-onset SMA being the most frequent and severe subtype.
SMA symptom severity is related to the effectiveness of the remaining SMN2 genes in compensating for the SMN1 deficiency, which is connected to the number of SMN2 gene copies on the chromosome. Healthy individuals have two SMN2 gene copies, while SMA patients can have one to four copies, with a higher number of copies associated with milder disease symptoms.
Onasemnogene abeparvovec, the only FDA-approved treatment for SMA, reduces symptom progression and improves motor function with continued use. Infants and young children treated with Onasemnogene abeparvovec have achieved developmental milestones and maintained them over time, with a decrease in breathing and nutrition difficulties and hospitalization rates. Older children and adults who received continuous Onasemnogene abeparvovec therapy have also benefited, including some who regained the ability to walk for longer distances, improved arm movement, and slowed or halted the condition's advancement.
Learn More About Onasemnogene Abeparvovec
Onasemnogene abeparvovec is a gene therapy drug that is administered as a single intravenous infusion. It uses recombinant adeno-associated virus serotype 9 vectors to deliver a functional copy of the human SMN gene. This therapy is designed to cross the blood-brain barrier and has been studied in an open-label, two-year phase 1 trial to evaluate its safety and effectiveness in treating patients with SMA type 1.
Before Starting Onasemnogene Abeparvovec
Before starting Onasemnogene abeparvovec, healthcare providers should perform a thorough medical evaluation of the patient, including a review of medical history, a physical examination, and laboratory tests.
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Patients need to be informed about the risks and benefits of Onasemnogene abeparvovec, including the potential for adverse reactions such as nausea, liver problems, low platelets, and transiently elevated levels of cardiac troponin-I.
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Patients receiving Onasemnogene abeparvovec should be closely monitored for signs and symptoms of thrombocytopenia, thrombotic microangiopathy, and elevated troponin-I levels, as well as any other potential adverse reactions.
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In addition, healthcare providers should consider the patient's vaccination status and adjust the vaccination schedule as needed to accommodate concomitant corticosteroid administration.
How Effective Is Onasemnogene Abeparvovec?
Pediatric patients with SMA type 1 who were treated with a single intravenous dose of Onasemnogene abeparvovec demonstrated a safety profile that could be monitored and managed for up to 6.2 years without any reports of treatment-related serious adverse events or adverse events of special interest. The therapy has shown sustained and long-lasting effectiveness in patients for up to 6.2 years after treatment. Ongoing and completed phase 3 and 4 studies are expected to further confirm the safety and effectiveness of Onasemnogene abeparvovec. Based on current evidence, the benefits of using this therapy for the treatment of pediatric patients with SMA outweigh the risks.
What Are the Things to Tell Physicians Before They Prescribe Onasemnogene Abeparvovec?
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Before starting treatment, it is important to inform the healthcare provider about any current or previous medical conditions, allergies, or medication intolerances.
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The patient should also disclose any ongoing medications, including prescription drugs, over-the-counter medications, vitamins, and herbal supplements.
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It is also important to disclose any previous treatments for SMA or other conditions, as well as any history of bleeding disorders or low platelet counts.
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Additionally, the healthcare provider should be informed of any history of liver disease or elevated liver enzymes, heart disease or cardiac abnormalities, or plans for future surgeries or procedures.
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The patient should also disclose any plans for vaccinations, particularly those that may be contraindicated for patients receiving corticosteroids, as well as any plans for pregnancy or current pregnancy status.
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Finally, the healthcare provider should be informed of any current or planned participation in other clinical trials.
Starting Onasemnogene Abeparvovec:
How to Take Onasemnogene Abeparvovec?
Onasemnogene abeparvovec is given as a single intravenous infusion in a hospital or clinical setting. The dosage and infusion duration will be determined by the consulting healthcare provider based on the patient's weight and medical history. It is important to follow the physician's instructions carefully and to report any adverse reactions or unexpected symptoms promptly. After administration, patients will be monitored for a period of time to ensure that there are no immediate adverse reactions. Patients may also need to have follow-up visits to monitor their response to the treatment.
Things to Do After Starting Onasemnogene Abeparvovec:
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Patients should be monitored for at least two hours after infusion of the drug for any adverse reactions or potential allergic reactions.
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Platelet count should be checked before infusion. If platelet count decreases significantly, additional monitoring may be necessary.
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Patients need to be monitored for thrombotic microangiopathy or thrombocytopenia, which may occur after infusion.
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Patients must take their routine vaccinations according to the Centers for Disease Control and Prevention (CDC) guidelines, with adjustments made if concomitant corticosteroid administration is necessary.
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Patients should avoid participation in activities with an increased risk of physical injuries, such as contact sports, for at least one month after infusion.
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Any new symptoms or side effects should be immediately reported to the treating physician.
What Are the Side Effects of Onasemnogene Abeparvovec?
According to clinical trials, some common side effects of Onasemnogene abeparvovec may include nausea and increased liver enzyme levels. On the other hand, serious adverse reactions such as liver issues and low platelet counts have also been reported. During clinical trials, there were also temporary increases in cardiac troponin-I levels, but it is uncertain whether this is clinically significant. However, animal studies have shown cardiac toxicity with this medication.
Due to the possibility of decreased platelet counts, platelet levels should be monitored prior to starting treatment and then weekly for the first month, followed by every two weeks for the next two months or until levels return to normal. Additionally, liver function should be monitored for a period of three months after administration.
For Doctors
Indication: Onasemnogene abeparvovec is indicated in children younger than two years of age with spinal muscular atrophy (SMA) type 1.
Pharmacology:
Mechanism of Action- Spinal muscular atrophy (SMA) is a genetic disorder that affects the neuromuscular system, resulting in decreased levels of SMN protein, which is required for the survival of motor neurons. Onasemnogene abeparvovec is a biological therapy that employs AAV9 virus capsids containing an SMN1 transgene and synthetic promoters. The SMN1 transgene delivers the AAV9 viral vector to the affected motor neurons upon infusion, increasing SMN protein levels.
Pharmacodynamics:
Absorption: Once Onasemnogene abeparvovec is infused into the patient's bloodstream, the viral vector carries the functional SMN1 gene to the patient's motor neuron cells. The absorption of Onasemnogene abeparvovec is not well documented in the literature, as it is a relatively new therapy. However, studies have shown that the therapy can result in increased SMN protein expression and improved motor function in patients with SMA.The therapy has a favorable safety profile, with few serious adverse events reported.
Metabolism: The metabolism of Onasemnogene abeparvovec has not been extensively studied in humans. However, preclinical studies have shown that the viral vector used to deliver the functional SMN1 gene, adeno-associated virus serotype 9 (AAV9), is primarily eliminated from the body through the liver. AAV9 is taken up by liver cells and then broken down by enzymes in the liver. The breakdown products of the AAV9 vector are then excreted in the urine and feces.
Elimination: As a gene therapy, Onasemnogene abeparvovec is designed to provide long-lasting benefits, and it is expected that the functional SMN1 gene will remain active in the patient's cells for an extended period of time. The elimination of Onasemnogene abeparvovec from the body has not been extensively studied in humans, as it is a relatively new therapy. However, preclinical studies have shown that the viral vector used to deliver the functional SMN1 gene, adeno-associated virus serotype 9 (AAV9), is primarily eliminated from the body through the liver.
Warnings and Precautions:
To manage Onasemnogene abeparvovec-induced hepatotoxicity, administering or increasing the corticosteroid dose may be effective, particularly if the drugs have been discontinued. Patients receiving the gene therapy should be closely monitored before and at regular intervals for at least three months. For infants with ALT or AST levels exceeding 10 times the ULN after receiving the therapy, a high dose of corticosteroids should be reinstated, followed by careful monitoring during subsequent dose reductions.
Dosage and Administration:
The medication is administered as a one-time, single IV infusion through a venous catheter. The recommended dose is 1.1 x 10^14 vector genomes per kilogram (vg/kg) of body weight. The prescribing information provides a weight-range dosing chart for dose calculation. For patients aged less than two years and weighing between 2.6 to 13.5 kg. For patients aged less than two years weighing 13.6 kg or more, the dose volume will require a combination of Onasemnogene abeparvovec kits.
Contraindications:
Onasemnogene abeparvovec is a gene therapy that is used to treat spinal muscular atrophy (SMA) in patients with specific genetic mutations. As with any medical treatment, there are certain contraindications or situations where it should not be used. The following are contraindications for Onasemnogene abeparvovec:
Allergy or Hypersensitivity: Patients who are allergic or hypersensitive to any of the components of Onasemnogene abeparvovec should not receive the therapy.
Pre-existing Liver Disease: Onasemnogene abeparvovec is primarily eliminated from the body through the liver. Therefore, patients with pre-existing liver disease or dysfunction may be at increased risk of adverse effects from the therapy.
Immune Deficiency Disorders: Patients with immune deficiency disorders, such as severe combined immunodeficiency (SCID) or acquired immunodeficiency syndrome (AIDS), may not be suitable candidates for Onasemnogene abeparvovec due to the potential risk of developing serious infections.
Pregnancy and Breast-feeding: The safety and efficacy of Onasemnogene abeparvovec have not been studied in pregnant or breastfeeding women. Therefore, it is recommended that these patients avoid receiving the therapy.
Drug Interactions:
Live Vaccines- When used in combination with Onasemnogene abeparvovec, the therapeutic efficacy of the Adenovirus type 7 vaccine is live. Anthrax vaccine, Bacillus calmette-guerin substrain Connaught live antigen, Bacillus calmette-guerin substrain Russian BCG-I live antigen, Bacillus calmette-guerin substrain TICE live antigen, BCG vaccine, Human adenovirus serotype 4 strain cl-68578 antigen, Rubella virus vaccine, and typhoid vaccine live can be decreased.
Other Specifications:
Onasemnogene Abeparvovec During Pregnancy: There is limited data available on the use of Onasemnogene abeparvovec during pregnancy, and it is not recommended for use in pregnant individuals. Animal studies have shown reproductive toxicity, and there is a theoretical risk of harm to the developing fetus. Women should also use effective contraception during treatment and for at least two months after receiving the medication.
Breastfeeding and Onasemnogene Abeparvovec: There is no available information on the excretion of Onasemnogene abeparvovec in human milk or its effects on breastfed infants. It is also unknown if Onasemnogene abeparvovec is absorbed systemically after oral ingestion. Due to the potential risk of harm to the infant, a decision should be made about whether to discontinue breastfeeding or discontinue the treatment with Onasemnogene abeparvovec. Before making any decisions about breastfeeding while receiving Onasemnogene abeparvovec treatment, it is necessary to consult a physician.
Onasemnogene Abeparvovec in Geriatric Patients: There is currently limited data on the use of Onasemnogene abeparvovec in geriatric patients. The safety and efficacy of this gene therapy have primarily been studied in pediatric patients with spinal muscular atrophy (SMA) type 1. As with any medical intervention, the potential benefits and risks of Onasemnogene abeparvovec in geriatric patients would need to be carefully evaluated by the treating physician based on the individual patient's medical history and current health status. A consultation with a medical geneticist or other SMA specialist may also be helpful in determining the appropriateness of this treatment in geriatric patients.
