Description for Itvisma
ITVISMA (onasemnogene abeparvovec-brve) is a suspension of an adeno-associated viral vector-based gene therapy for intrathecal injection. It is a recombinant self-complementary AAV9 containing a transgene encoding the human survival motor neuron (SMN) protein, under the control of a cytomegalovirus enhancer/chickenβactin hybrid promoter.
ITVISMA has a nominal concentration of 4 × 1013 vg/mL. Each vial contains an extractable volume of not less than 3 mL and the excipients 20 mM Tris (pH 8.0), 1 mM magnesium chloride (MgCl2), 200 mM sodium chloride (NaCl) and 0.005% poloxamer 188. ITVISMA is packaged as a sterile suspension and contains no preservative.
ADVERSE REACTIONS
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 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 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 1014 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.
Table 3: Adverse Reactions Occurring in ≥2% of Patients or with higher frequency in ITVISMA-treated
Patients compared to Sham group in Study 1
| Adverse reactions | ITVISMA (N = 75), n (%) |
Sham (N = 51), n (%) |
| Upper respiratory tract infection* | 31 (41) | 15 (29) |
| Pyrexia | 19 (25) | 12 (24) |
| Upper gastrointestinal symptoms* | 20 (27) | 8 (16) |
| Hepatic enzyme increased* | 6 (8)a | 5 (10) |
| Headache | 8 (11) | 2 (4) |
| Dizziness | 4 (5) | 1 (2) |
| Pain in extremity | 3 (4) | 1 (2) |
| Thrombocytopenia* | 3 (4) | 0 |
| Sensory disturbance* | 2 (3)b | 1 (2)c |
| * Is a composite that includes multiple related terms a) Two patients had ALT elevations of 20 times the upper limit of normal (ULN) b) Signs and symptoms that may be suggestive of dorsal root ganglion (DRG) toxicity occurred within 3 weeks of ITVISMA injection and stabilized but remained unresolved at the end of study period. c) Occurred 154 days after the sham procedure and resolved after 15 days without intervention. |
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The safety evaluated in Study 2 did not identify any additional safety events with ITVISMA administration.
Postmarketing Experience
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
Drug Interactions for Itvisma
Adjust patient’s vaccination schedule to accommodate concomitant corticosteroid administration prior to and following ITVISMA injection [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).
Warnings for Itvisma
Included as part of the PRECAUTIONS section.
Precautions for Itvisma
Hepatotoxicity
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.
Thrombocytopenia
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
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
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.
Elevated Cardiac Troponin I
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 . Consider cardiac evaluation after ITVISMA administration and consult a cardiologist as needed.
AAV Vector Integration and Risk of Tumorigenicity
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.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
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 × 1014 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.
Animal Toxicology and/or Pharmacology
A single intrathecal (IT) dose of onasemnogene abeparvovec was administered at three dose levels: 1.20 × 10¹³ vg/animal (equivalent to the clinical therapeutic dose), 3.0 × 1013 vg/animal, and 6.0 × 1013 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.
Clinical Pharmacology for Itvisma
Mechanism of Action
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.
Pharmacodynamics
There are no clinically relevant pharmacodynamics data for ITVISMA.
Pharmacokinetics
Nonclinical Biodistribution
Intrathecal (IT) administration of onasemnogene abeparvovec to non-human primates (NHPs) at dose levels of 1.2 × 1013 (equivalent to the clinical therapeutic dose), 3.0 × 1013, or 6.0 × 1013 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 × 1013 and 3.0 × 1013 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.
Immunogenicity
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.
Patient Information for Itvisma
Hepatotoxicity
Inform patients and caregivers that ITVISMA could increase liver enzyme levels. Inform patients and caregivers that patients will receive an oral corticosteroid medication before and after ITVISMA injection, and will undergo regular blood tests to monitor liver function. Advise patients and 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 [see Warnings and Precautions (5.1)].
Vaccination Before and After ITVISMA Injection
Advise patients and caregivers to consult with their healthcare provider to determine if adjustments to the patient’s vaccination schedule are necessary during corticosteroid use. Inform patients and 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 ITVISMA administration. Please consult your health care provider [see Dosage and Administration (2.1), Drug Interactions (7)].
Concurrent Infections
Patients and caregivers should be aware that an infection (e.g., cold, flu, gastroenteritis, otitis media, bronchiolitis, etc.) before or after ITVISMA injection could lead to more serious complications. Patients, caregivers and close contacts of patients should follow infection prevention practices (e.g., hand hygiene, coughing/sneezing etiquette, limiting potential contacts). Advise patients and caregivers of the signs of a possible infection, such as coughing, wheezing, sneezing, runny nose, sore throat, or fever. Patients and caregivers should contact their healthcare provider immediately if the patient experiences any symptoms suggestive of infection before or after ITVISMA injection [see Dosage and Administration (2.1)].
Thrombocytopenia
Inform patients and caregivers that ITVISMA could decrease blood platelet count and increase the risk of bruising or bleeding. Inform patients and caregivers that decreases in platelet counts were observed within the first week after ITVISMA injection. Advise patients and caregivers to seek medical attention if the patient experiences unexpected bruising or bleeding [see Warnings and Precautions (5.2)].
Peripheral Sensory Neuropathy
Inform patients and caregivers that peripheral sensory neuropathy has occurred with ITVISMA administration. Advise patients and caregivers to contact their healthcare provider promptly if the patient experiences numbness, tingling, prickling, or pain in the arms, hands, legs and/or feet [see Warnings and Precautions (5.3)].
Thrombotic Microangiopathy
Inform patients and/or caregivers that decreased blood platelet and red blood cell counts, acute kidney injury, and increased bruising or bleeding, which may be indicative of TMA, can occur. Advise patients and/or caregivers to seek immediate medical attention if the patient experiences unexpected bruising or bleeding, seizures, or decreased urine output [see Warnings and Precautions (5.4)].
AAV Vector Integration and Risk of Tumorigenicity
Inform patients and/or caregivers that there is a theoretical risk of tumorigenicity with AAV therapies such as ITVISMA. Advise patients and/or caregivers to contact their healthcare provider and Novartis Gene Therapies, Inc. (1-833-828-3947) if the patient who received ITVISMA develops a tumor [see Warnings and Precautions (5.6)].
Contraception and Egg/Sperm Donation
Advise women of childbearing potential to use an effective method of contraception and to refrain from egg donation for 6 months following ITVISMA injection. Advise men capable of fathering a child to use a barrier method of contraception and to refrain from sperm donation for 3 months following ITVISMA injection [see Use in Specific Populations (8.3)].
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