Get your patient on Itvisma (Onasemnogene Abeparvovec-Brve)

For single-dose intrathecal injection only.

• Patients previously treated with ZOLGENSMA (onasemnogene abeparvovec-xioi) should not be treated with ITVISMA [see Clinical Pharmacology (12.1)] .
• ITVISMA should only be administered intrathecally using a lumbar puncture by healthcare professionals (e.g., interventional radiologist or neurologist) experienced in performing lumbar punctures.
• Prior to ITVISMA injection:
  • Due to the increased risk of serious systemic immune response, administer ITVISMA to patients who are clinically stable in their overall baseline health status (e.g., hydration and nutritional status, absence of infection, respiratory status) prior to administration. Postpone ITVISMA in patients with active or recent 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 ITVISMA injection.
  • Assess vaccination status. Vaccination status should be up-to-date prior to ITVISMA administration. Recommend seasonal prophylaxis against respiratory syncytial virus (RSV).
  • Assess liver function (clinical examination and laboratory testing including aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, prothrombin time, partial thromboplastin time (PTT), international normalized ratio (INR), and total bilirubin) [see Warnings and Precautions (5.1), Use in Specific Populations (8.6)] .
  • Obtain creatinine and complete blood count (including hemoglobin and platelet count) [see Warnings and Precautions (5.2, 5.4)] .
  • Perform baseline testing for the presence of anti-AAV9 antibodies.
• One day prior to ITVISMA injection, 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. Do not stop systemic corticosteroids abruptly. After the 30-day period, taper prednisolone (or equivalent) as needed according to the clinical status and liver function testing [see Warnings and Precautions (5.1, 5.2)] . See Table 1 for the recommended corticosteroid regimen.
• Do not re-administer ITVISMA.

The recommended dose of ITVISMA is 1.2 × 10 ¹⁴ vector genomes (vg).

Table 1 includes the recommended corticosteroid regimen prior to and following ITVISMA injection.

If at any time patients do not respond adequately to the equivalent of 1 mg/kg/day oral prednisolone, based on the patient’s clinical course, obtain prompt consultation with a gastroenterologist or hepatologist and consider adjustment to the recommended corticosteroid regimen, including increased dose, longer duration or prolongation of corticosteroid taper [see Warnings and Precautions (5.1)] . If oral corticosteroid therapy is not tolerated or not effective, consider intravenous corticosteroids, as clinically indicated.

Required supplies and materials (not supplied)

• Needle for withdrawal
• Syringe
• Syringe cap
• Spinal needle

The supplies and materials compatible with ITVISMA are listed in Table 2. Device components must be indicated for intrathecal or neuraxial use. Ensure all device components use the same connector type. Incompatible device connections may result in dose loss during administration.

Vial Preparation:

• ITVISMA should be prepared aseptically.
• Thaw ITVISMA in the refrigerator for approximately 4 hours, or at room temperature for approximately 1 hour. If thawed in the refrigerator, remove ITVISMA from refrigerator on day of dosing.
• Do not use ITVISMA unless thawed.
• Prior to intrathecal injection, ITVISMA should be brought to room temperature.
• When thawed, ITVISMA is a clear to slightly opaque, colorless to faint white liquid, free of particles. After withdrawal of ITVISMA from the vial, a visual inspection is required. DO NOT use if particulates, cloudiness, or discoloration are visible.
• DO NOT SHAKE.
• Immediately prior to dosing, draw the content from the vial into the syringe, remove air from syringe, confirm the dose volume of 3 mL in the syringe, cap syringe and deliver to patient injection location.
• Once dose is drawn into the syringe, it may be held in the refrigerator at 2°C to 8°C (36°F to 46°F) for up to 24 hours, including a 5-hour maximum time out-of-refrigeration allowance within the 24-hour period. Discard the vector-containing syringe if not injected within this time period.
• DO NOT REFREEZE.

Procedural Preparation Instructions:

• Consider sedation if indicated by the patient’s clinical status.
• Consider imaging techniques to guide intrathecal injection of ITVISMA.
• Evaluate patient prior to and after intrathecal injection for conditions that may contraindicate lumbar puncture or increase procedural risk to prevent serious complications.

Intrathecal Injection Instructions:

• Prior to administration, remove 3 mL of cerebrospinal fluid (CSF) using a lumbar puncture needle to create space for injection volume.
• Administer ITVISMA as an intrathecal bolus injection over approximately 1 to 2 minutes through the lumbar puncture needle.
• Place patient in Trendelenburg position (head down at 30 degrees for 15 minutes). Adjust patient positioning and duration based on the patient’s clinical status to enhance distribution.
• Follow standard post-lumbar puncture care protocols.

Monitoring Following ITVISMA Injection:

• Liver function (AST, ALT, total bilirubin) weekly for the month after ITVISMA injection and during the corticosteroid taper period (over the next 28 days or longer if needed). If the patient is clinically stable with unremarkable findings (normal clinical exam, total bilirubin, and ALT and AST levels below 2 × ULN) at the end of the corticosteroid taper period, continue to monitor liver function every other week for another month [see Warnings and Precautions (5.1)] .
• Platelet counts weekly for the first month and as clinically indicated until platelet counts return to baseline [see Warnings and Precautions (5.2)] .

Risk Summary

There are no clinical studies in pregnant women to inform a product-associated risk. There are no available data in animal embryo-fetal development studies with ITVISMA. It is not known whether ITVISMA has the potential to be transferred to the fetus. Therefore, women who are pregnant or desire to become pregnant should only be treated with ITVISMA after a thorough benefit-risk evaluation.

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.

Risk Summary

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

Pregnancy Testing

The pregnancy status of females of reproductive potential should be verified prior to treatment with ITVISMA [see Use in Specific Populations (8.1)] .

Contraception

Females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) and should refrain from egg donation for 6 months following ITVISMA administration. Men capable of fathering a child should use a barrier method of contraception and should refrain from sperm donation for 3 months following ITVISMA administration.

Infertility

There is no data on the effect of ITVISMA on human fertility. In animal fertility studies, onasemnogene abeparvovec did not impact fertility in male and female mice at a dose of 1.1 × 10 ¹⁴ vg/kg administered intravenously [see Nonclinical Toxicology (13.1)] .

The safety and efficacy of ITVISMA have been established in pediatric patients 2 years of age and older. The use of ITVISMA was supported by data from one clinical study (Study 1) which enrolled 126 pediatric patients 2 years of age and older [see Adverse Reaction (6) and Clinical Studies (14)] .

The safety and effectiveness of ITVISMA have not been established in pediatric patients younger than 2 years of age.

Patients with preexisting hepatic impairment or acute hepatic viral infection may be at higher risk of liver injury. ITVISMA therapy should be carefully considered in patients with liver impairment [see Warnings and Precautions (5.1)] .

Hepatotoxicity, with elevated ALT and/or AST levels, has occurred with ITVISMA [see Adverse Reactions (6.1)] . Patients with preexisting hepatic impairment or acute hepatic viral infection may be at higher risk of liver injury. In order to mitigate potential aminotransferase elevations, administer systemic corticosteroid before and after ITVISMA injection. 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 (2.2)] .

Prior to ITVISMA injection, assess liver function by clinical examination and laboratory testing. Continue to monitor liver function for at least 3 months after ITVISMA administration, and at other times as clinically indicated. Monitor AST, ALT and total bilirubin weekly for the month after ITVISMA administration and during the corticosteroid taper period. 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. Tapering of systemic corticosteroids should not be considered until AST/ALT levels are less than 2 × ULN [see Dosage and Administration (2.1, 2.4)] .

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 is recommended (e.g., albumin, prothrombin time, partial thromboplastin time (PTT) and international normalized ratio (INR)). Promptly consult with a gastroenterologist or hepatologist, as necessary.

Transient decreases in platelet counts were observed within the first week after ITVISMA administration [see Adverse Reactions (6.1)] . The platelets counts are expected to return to baseline two weeks following ITVISMA injection.

Monitor platelet counts before ITVISMA injection and on a regular basis afterwards (at least weekly for the first month and as clinically indicated until platelet counts return to baseline) [see Dosage and Administration (2.1, 2.4)] .

Peripheral sensory neuropathy has occurred with ITVISMA administration [see Adverse Reactions (6.1)] . Signs and symptoms may include numbness, tingling, prickling, or pain in the arms, hands, legs and/or feet, with onset seen at approximately three weeks post-injection in clinical studies.

Consider complete neurologic evaluation and other testing and/or symptom management based on the patient's clinical presentation. Inform patients and caregivers about the signs and symptoms of peripheral sensory neuropathy, and advise patients and caregivers to notify their physician promptly if such symptoms occur.

Thrombotic microangiopathy (TMA) may occur with ITVISMA administration. TMA is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury. Concurrent immune system activation (e.g., infections, vaccinations) may be a contributing factor.

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

Monitor platelet counts on a regular basis following ITVISMA injection [see Warnings and Precautions (5.2)] , as well as signs and symptoms of TMA, such as hypertension, bruising easily, 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 hematologist and/or nephrologist immediately to manage TMA as clinically indicated.

Increases in cardiac troponin I levels have occurred following ITVISMA administration without clinical sequelae [see Adverse Reactions (6.1)] . Cardiac toxicity was observed in animal studies [see Nonclinical Toxicology (13.2)] . Consider cardiac evaluation after ITVISMA administration and consult a cardiologist as needed.

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

ITVISMA 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 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. If a tumor develops in a patient receiving ITVISMA, health care providers should contact and report the tumor to Novartis Gene Therapies, Inc. at 1-833-828-3947.

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 reflects exposure of ITVISMA in two clinical studies, Study 1, a randomized, sham-controlled study which evaluated the safety of ITVISMA in 126 patients with spinal muscular atrophy (SMA) and Study 2, an open-label-single arm study which evaluated safety of ITVISMA in 27 patients with SMA who were previously treated with nusinersen (at least 4 months washout) or risdiplam (at least 15 days washout). In Study 1, a total of 75 patients received a single intrathecal injection of ITVISMA at a fixed dose of 1.2 x 10 ¹⁴ vg and 51 patients underwent a sham-procedure [see Clinical Studies (14)] . In Study 2, a total of 27 patients received a single intrathecal injection of ITVISMA at a fixed dose of 1.2 x 10 ¹⁴ vg. The patients were followed for a duration of 52 weeks for both studies.

In Study 1, serious adverse reactions were reported in four patients (5%) including elevated liver enzymes (n=1), sensory disturbance (n=2), and vomiting (n=1).

The most frequent adverse reactions occurring in ≥ 2% of patients in Study 1 are summarized in Table 3 below.

The safety evaluated in Study 2 did not identify any additional safety events with ITVISMA administration.

The following adverse reactions have been identified during post-approval use of ZOLGENSMA, a similar product containing the same active ingredient (onasemnogene abeparvovec) administered intravenously. 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

Hepatobiliary Disorders : acute liver failure (fatal and non-fatal), acute liver injury

General Disorders and Administration Site Conditions : pyrexia, infusion-related reactions

Investigations : troponin increased

ITVISMA is a non-replicating recombinant AAV vector that utilizes AAV9 capsid to deliver a functional copy of human survival motor neuron 1 gene (SMN1) . The transgene DNA persists largely in episomal form in the nucleus of transduced cells. Expression of the transgene is driven by a constitutive promoter (cytomegalovirus enhanced chicken β actin hybrid), resulting in continuous and sustained SMN expression. SMA is caused by a bi-allelic mutation in the SMN1 gene, which results in insufficient SMN protein expression. By providing an alternative source of SMN protein expression in motor neurons, it is expected to promote the survival and function of transduced motor neurons.

There are no clinically relevant pharmacodynamics data for ITVISMA.

Nonclinical Biodistribution

Intrathecal (IT) administration of onasemnogene abeparvovec to non-human primates (NHPs) at dose levels of 1.2 × 10 ¹³ (equivalent to the clinical therapeutic dose), 3.0 × 10 ¹³ , or 6.0 × 10 ¹³ vector genomes (vg)/animal, resulted in biodistribution of the vector to all the CNS and peripheral tissues assessed. Vector DNA concentrations were highest in the liver, followed by the dorsal root ganglia (DRG) and spinal cord, with the lowest concentrations detected in the gonads. Vector DNA concentrations in the spinal cord tended to remain stable between 6-weeks and 12-months post-administration at all dose levels assessed.

Intrathecal or intra-cisterna magna administration of a tool scAAV9CB-GFP vector to adult NHPs resulted in the detection of vector DNA in the oocytes and ovarian stromal cells of females administered 1.0 × 10 ¹³ and 3.0 × 10 ¹³ vg/animal at 28-days post-administration of the product. In mice, IV, or intracerebroventricular (ICV) administration of onasemnogene abeparvovec resulted in no detection of vector DNA in the germline cells of males and females at 24 weeks post-administration.

In non-human primates, high pre-existing serum anti-AAV9 antibody titers (corresponding to human titer values of up to approximately 1:25000) were not shown to affect scAAV9 vector (utilized in onasemnogene abeparvovec) DNA distribution in the spinal cord following intrathecal administration.

Clinical Vector Shedding

ITVISMA vector shedding studies, which assess the amount of vector DNA eliminated from the body through saliva, urine, feces and nasal secretions were performed following intrathecal administration in 134 patients.

Vector DNA was detectable in shedding samples in 134 patients following intrathecal injection of ITVISMA. Shedding of onasemnogene abeparvovec DNA was primarily via feces. Peak shedding in participants was observed within 10-, 3-, 2-, and 8 days post-dose for stool, urine, saliva and nasal secretion, respectively. The majority of the vector DNA (> 90%) is excreted within 2 weeks after dose administration.

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of ITVISMA or of other AAV gene therapy products.

In Study 1 and Study 2, anti-AAV9 antibody titers were evaluated in 102 patients following a single intrathecal injection of ITVISMA. In these studies, patients were required to have baseline anti-AAV9 antibody titers ≤ 1:50.

Increases from baseline in anti-AAV9 antibody titers were reported in all patients with a median anti-AAV9 antibody titers of ≥ 1:819,200 at 12 months following ITVISMA injection in both studies.

During the 12-month period following ITVISMA injection in Study 1 and Study 2, positive anti-SMN antibodies were observed in 5/75 (6.7%) and 2/27 (7.4%) of ITVISMA-treated patients, respectively. There was no identified clinical effect of anti-SMN and anti-AAV9 antibodies on safety or efficacy of ITVISMA over the follow-up period of 12 months post-dose.

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

In fertility and early embryonic development studies conducted in male and female mice, intravenous administration of onasemnogene abeparvovec at dose levels up to 1.1 × 10 ¹⁴ vector genomes (vg)/kg body weight had no effect on fertility, fecundity, or mating indices. There was no evidence of germ cell transduction or germline transmission.

A single intrathecal (IT) dose of onasemnogene abeparvovec was administered at three dose levels: 1.20 × 10 ¹³ vg/animal (equivalent to the clinical therapeutic dose), 3.0 × 10 ¹³ vg/animal, and 6.0 × 10 ¹³ vg/animal. At 6 weeks post-administration, all dose levels resulted in acute, minimal to moderate mononuclear cell inflammation and neuronal degeneration across multiple anatomical sites, including the cerebrum, cerebellar white matter, brain stem, dorsal root ganglia (DRG), and various nerve structures (trigeminal, dorsal spinal, spinal, and peripheral nerves). Additionally, axonal degeneration and/or gliosis was observed in the spinal cord. These findings partially or fully resolved by 12 months post-administration and had no correlative clinical observations. Elevated liver enzyme levels (aspartate and alanine amino transferase) and single cell necrosis of hepatocytes were observed in select NHPs at 6 weeks post-administration but resolved by 12 months post-administration.

ITVISMA is supplied as a sterile, preservative-free, clear to slightly opaque, colorless to faint white suspension for intrathecal injection. ITVISMA contains 4 × 10 ¹³ vg per mL.

Each carton of ITVISMA contains a single-dose vial with an extractable volume of not less than 3 mL, containing 1.2 × 10 ¹⁴ vg.

Carton containing one 1.2 × 10 ¹⁴ vg/3 mL (4 × 10 ¹³ vg/mL) single-dose vial.

Container (vial): NDC Number 71894-200-01

Package (carton): NDC Number 71894-200-02

• Product is shipped and delivered frozen (≤ -60°C [-76°F]) in a single-dose clear vial.
• Upon receipt, immediately place the carton in a refrigerator at 2°C to 8°C (36°F to 46°F).
• ITVISMA 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.