Leaflet ITVISMA 1.2x1014vector genomes / ml solution for injection
- Product code:
- W72070001
- Quantity:
- 1
- Indicated for:
- spinal muscular atrophy
- Route of administration:
- injectable
- Substance:
- onasemnogen abeparvovec (gene therapy)
- ATC
- M09AX09 — Musculo-skeletal system | Other drugs for disorders of the musculo-skeletal system | Other drugs for disorders of the musculo-skeletal system
The medication is administered as a single intravenous infusion, as directed by a doctor. It is important for patients to be closely monitored before and after administration to prevent potential complications.
Patients should be aware of potential side effects, such as elevated liver enzymes, vomiting, or fever. It is important to inform the doctor of any unusual symptoms.
Common side effects include elevated liver enzymes, vomiting, fever, and decreased appetite. In rare cases, severe reactions such as liver failure or allergic reactions may occur. Patients should be informed of these risks before starting treatment.
General data about ITVISMA 1.2x1014vector genomes / ml
- Substance:
- onasemnogen abeparvovec
- Date of latest medicines list:
- 01-08-2026
- Product code:
- W72070001
- Concentration:
- 1.2x1014vector genomes / ml
- Pharmaceutical form:
- solution for injection
- Quantity:
- 1
- Product type:
- Original
- Prescription status:
- P-RF — Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Pharmaceutical forms available for onasemnogen abeparvovec
Concentrations available for onasemnogen abeparvovec
- 1.2x1014vector genomes/ml
- 2x10^13vector genomes/ml
Official documents
- Added to database:
- 28/07/2026
Contents of the package leaflet for the medicine ITVISMA 1.2x1014vector genomes / ml solution for injection
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Leaflet ITVISMA 1.2x1014vector genomes/ml
1. NAME OF THE MEDICINAL PRODUCT
Itvisma 1.2 × 1014 vector genomes solution for injection
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
2.1 General description
Onasemnogene abeparvovec is a gene therapy medicinal product that expresses the human survivalmotor neuron (SMN) protein. It is a non-replicating recombinant adeno-associated virus serotype 9(AAV9) based vector containing the cDNA of the human SMN gene under the control of thecytomegalovirus enhancer/chicken-β-actin-hybrid promoter.
Onasemnogene abeparvovec is produced in human embryonic kidney cells by recombinant DNAtechnology.
2.2 Qualitative and quantitative composition
Each single-dose vial contains 1.2 × 1014 vector genomes (vg) of onasemnogene abeparvovec in 3 mLof solution. Onasemnogene abeparvovec intrathecal injection has a nominal concentration of4 × 1013 vg/mL, and each vial contains an extractable volume of not less than 3 mL.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Solution for injection.
A clear to slightly opaque, colourless to faint white solution with a pH of 7.7 to 8.3 and osmolality of390 to 430 mOsm/kg.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Itvisma is indicated for the treatment of 5q spinal muscular atrophy (SMA) with a bi-allelic mutationin the SMN1 gene in patients 2 years of age and older.
4.2 Posology and method of administration
Treatment should be initiated and administered in clinical centres and supervised by a physicianexperienced in the management of patients with SMA.
Before administration of Itvisma, baseline laboratory testing is required, including, but not limited to:
* AAV9 antibody testing using an appropriately validated assay (see section 4.4),
* liver function: alanine aminotransferase (ALT), aspartate aminotransferase (AST), and totalbilirubin (see section 4.4),
* creatinine, and
* complete blood count (including haemoglobin and platelet count) (see section 4.4).
It is recommended that patients are clinically stable in their overall health status prior to injection (seesection 4.4). The benefit-risk profile of Itvisma in patients with respiratory failure, on permanentventilation, and/or unable to swallow is not established.
Because the treatment persists in non-dividing cells, patients previously treated with onasemnogeneabeparvovec (any route of administration) should not be treated with Itvisma (see section 5.1).
PosologyItvisma is administered as a single dose of 1.2 × 1014 vg.
Immunomodulatory regimen
To dampen an immune response, immunomodulation with corticosteroids is recommended. Elevationsin liver aminotransferases or decreased platelet counts may occur following treatment (see sections 4.4and 4.8). Where feasible, the patient’s vaccination schedule should be adjusted to accommodateconcomitant corticosteroid administration prior to and following Itvisma injection (see section 4.5).
Table 1 shows the recommended immunomodulatory regimen prior to and following injection.
Table 1 Recommended immunomodulatory regimen pre- and post-injection
Pre-injection 24 hours prior to Itvisma injection Prednisolone orally 1 mg/kg/day(or equivalent)
Post-injection 30 days (including the day of Itvisma Prednisolone orally 1 mg/kg/dayadministration) (or equivalent)
Followed by 28 days: Systemic corticosteroids should betapered gradually.
For patients with unremarkable findings(normal clinical exam, total bilirubin, and Taper prednisolone (or equivalentwhose ALT and AST values are both below if another corticosteroid is used),2 × upper limit of normal (ULN)) at the end e.g. by decrements ofof the 30 days period: 0.20 mg/kg/day per week over atleast 4 weeks for oral prednisoloneor
For patients with liver function Systemic corticosteroidsabnormalities at the end of the 30 days (equivalent to oral prednisoloneperiod: continuing until the AST and ALT 1 mg/kg/day)values are below 2 × ULN and all otherassessments (e.g. total bilirubin) return to Systemic corticosteroids should benormal range, followed by tapering over tapered gradually.
28 days or longer if needed.
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, prompt consultation with a gastroenterologist or hepatologistand adjustment to the recommended immunomodulatory regimen, including increased dose, longerduration or prolongation of corticosteroid taper, may be considered (see section 4.4). If oralcorticosteroid therapy is not tolerated or not effective, intravenous corticosteroids may be consideredas clinically indicated.
If another corticosteroid is used by the physician in place of prednisolone, similar considerations andapproach to taper the corticosteroid dose after 30 days should be taken as appropriate.
Special populationsRenal impairment
The safety and efficacy of Itvisma have not been established in patients with renal impairment. A doseadjustment should not be considered.
Hepatic impairmentItvisma therapy should be carefully considered in patients with hepatic impairment (see section 4.4). Adose adjustment should not be considered.
Paediatric populationThe safety and efficacy of Itvisma in children aged under 2 years have not been established. Currentlyavailable data are described in sections 4.8 and 5.1 but no recommendation on a posology can be madein children aged 6 months to ˂ 2 years. No data are available in children aged ˂ 6 months.
Adult population
No clinical study data are available in patients aged 18 years and older.
Method of administrationFor intrathecal use. Treatment should be administered intrathecally using a lumbar puncture byhealthcare professionals experienced in performing lumbar punctures.
* Immediately prior to dosing, draw the content from the vial into the syringe, remove air fromthe syringe, confirm the dose volume of 3 mL in the syringe, cap the syringe and deliver to thepatient injection location.
* If indicated by the patient’s clinical status, sedation should be considered.
* Imaging techniques to guide intrathecal injection may be considered.
* The patient should be evaluated prior to and after intrathecal injection for the presence ofpotential conditions related to lumbar puncture, to avoid serious procedural complications.
* Prior to administration, remove 3 mL of cerebrospinal fluid (CSF) using a lumbar punctureneedle.
* Itvisma is administered as a single-dose bolus intrathecal injection over approximately 1 to2 minutes.
* Following intrathecal injection, placement in Trendelenburg position (depending on thepatient’s clinical status) is recommended.
For detailed instructions on the preparation, handling, accidental exposure and disposal of themedicinal product, see section 6.6.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.
Reasons to postpone treatment
Due to the risk of serious immune response, it is recommended that patients are clinically stable intheir overall health status (e.g. hydration and nutritional status, absence of infection, respiratory status)prior to injection. Itvisma should be postponed in patients with infection, either acute (e.g. respiratory)or chronic uncontrolled, until the infection has resolved and the patient is clinically stable. Clinicalsigns or symptoms of infection should not be evident at the time of injection.
Pre-existing immunity against AAV9
In Itvisma clinical studies, patients were required to have baseline serum anti-AAV9 antibody titres≤ 1:50. The safety and efficacy of Itvisma in patients with elevated anti-AAV9 antibody titres have notbeen evaluated in humans.
HepatotoxicityHepatotoxicity, which generally manifested as elevated ALT and/or AST levels, has occurred withonasemnogene abeparvovec intrathecal injection (see section 4.8). In order to mitigate potentialaminotransferase elevations, a systemic corticosteroid should be administered to all patients beforeand after intrathecal injection. Immune-mediated hepatotoxicity may require adjustment of theimmunomodulatory regimen including longer duration, increased dose, or prolongation of thecorticosteroid taper (see section 4.2).
Patients with pre-existing hepatic impairment or acute hepatic viral infection may be at higher risk ofliver injury. Patients with elevated liver function tests have not been studied in clinical studies withonasemnogene abeparvovec intrathecal injection.
Prior to onasemnogene abeparvovec intrathecal injection, liver function of all patients should beassessed by clinical examination and laboratory testing. Liver function should be monitored for at least3 months after onasemnogene abeparvovec intrathecal injection administration, and at other times asclinically indicated. AST, ALT and total bilirubin should be assessed weekly for the first month afteronasemnogene abeparvovec intrathecal injection administration and during the corticosteroid taperperiod. If the patient is clinically stable with unremarkable findings at the end of the corticosteroidtaper period, liver function should continue to be monitored every two weeks for another month.
Tapering of systemic corticosteroids should not be considered until AST/ALT levels are less than2 × ULN (see section 4.2).
Patients with worsening liver function test results and/or signs or symptoms of acute illness should bepromptly clinically assessed and monitored closely. In case hepatic injury is suspected, further testingis recommended (e.g. albumin, prothrombin time, PTT and INR). Prompt consultation with agastroenterologist or hepatologist is recommended, as necessary.
ThrombocytopeniaTransient decreases in platelet counts were typically observed within the first week afteronasemnogene abeparvovec intrathecal injection administration. In most cases, platelet counts were˃ 75 × 109/L and returned to baseline two weeks following onasemnogene abeparvovec intrathecalinjection.
Platelet counts should be obtained before onasemnogene abeparvovec intrathecal injection and shouldbe monitored on a regular basis afterwards, at least weekly for the first month and as clinicallyindicated until platelet counts return to baseline.
Thrombotic microangiopathy
Thrombotic microangiopathy (TMA) may occur. TMA is characterised by thrombocytopenia,microangiopathic haemolytic anaemia 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 orfatal outcomes.
Thrombocytopenia is a key feature of TMA, therefore platelet counts should be monitored on a regularbasis following onasemnogene abeparvovec intrathecal injection, as well as signs and symptoms of
TMA, such as hypertension, bruising easily, seizures or decreased urine output. In case these signs andsymptoms occur in the presence of thrombocytopenia, further diagnostic evaluation for haemolyticanaemia and renal dysfunction should be promptly undertaken. If clinical signs, symptoms and/orlaboratory findings consistent with TMA occur, a haematologist and/or nephrologist should beconsulted immediately to manage TMA as clinically indicated. Patients and caregivers should beinformed about signs and symptoms of TMA and should be advised to seek urgent medical care ifsuch symptoms occur.
Peripheral sensory neuropathy
Peripheral sensory neuropathy has occurred with onasemnogene abeparvovec intrathecal injection.
Administration of onasemnogene abeparvovec intrathecal injection may result in sensory symptoms(e.g. numbness, tingling, prickling or pain in the arms, hands, legs and/or feet), with onset seen atapproximately three weeks post-injection in clinical studies. Symptoms requiring management withadditional therapies may persist, but can also gradually improve over time (see section 4.8). Sensorysymptoms suggestive of peripheral sensory neuropathy may also occur as part of the natural course of
SMA.
Complete neurological evaluation and other testing and/or symptom management should beconsidered based on the patient’s clinical presentation. Patients and caregivers should be informedabout the signs and symptoms of peripheral sensory neuropathy and be advised to notify theirphysician promptly if such symptoms occur.
Risk of tumourigenicity as a result of vector integration
There is a theoretical risk of tumourigenicity due to potential integration of the AAV vector DNA ofonasemnogene abeparvovec into the host genome.
Onasemnogene abeparvovec intrathecal injection is composed of a non-replicating AAV9 vectorwhose DNA persists largely in episomal form. Random integration of recombinant AAV-vector DNAinto human DNA has been reported with AAV gene therapies. The clinical relevance of individualintegration events is unknown, but it is acknowledged that individual integration events couldpotentially contribute to a risk of tumourigenicity.
So far, no cases of malignancies associated with onasemnogene abeparvovec intrathecal injectiontreatment have been reported. In the event of a tumour, the marketing authorisation holder should becontacted for guidance on collecting patient samples for testing.
Blood, organ, tissue and cell donation
Patients treated with onasemnogene abeparvovec intrathecal injection should not donate blood, organs,tissues or cells for transplantation.
Sodium contentThis medicinal product contains less than 1 mmol sodium (23 mg) per 3 mL dose, that is to sayessentially ‘sodium-free’.
4.5 Interaction with other medicinal products and other forms of interaction
No interaction studies have been performed.
VaccinationsWhere feasible, the patient’s vaccination schedule should be adjusted to accommodate concomitantcorticosteroid administration prior to and following onasemnogene abeparvovec intrathecal injection.
Seasonal respiratory syncytial virus (RSV) prophylaxis is recommended. Live vaccines, such asmeasles, mumps and rubella (MMR) and varicella, should not be administered to patients on animmunosuppressive steroid dose (i.e. ≥ 2 weeks of daily receipt of 20 mg or 2 mg/kg body weight ofprednisolone or equivalent).
4.6 Fertility, pregnancy and lactation
There are no data from the use of onasemnogene abeparvovec in pregnant women. Animal studies donot indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Itis not known whether onasemnogene abeparvovec has the potential to be transferred to the foetus inhumans. Therefore, women who are pregnant or may become pregnant should only be treated with
Itvisma after a thorough benefit-risk evaluation.
Breast-feedingThere is no information available on the presence of onasemnogene abeparvovec in human milk, theeffects on the breast-fed infant or the effects on milk production. A decision must be made whether todiscontinue breast-feeding, taking into account the benefit of breast-feeding for the child and thebenefit of therapy for the woman.
FertilityThere are no data on the effect of onasemnogene abeparvovec on human fertility. In animal fertilitystudies, onasemnogene abeparvovec did not impact fertility in male or female mice at doses up to1.1 × 1014 vg/kg administered intravenously (see section 5.3).
4.7 Effects on ability to drive and use machines
Onasemnogene abeparvovec intrathecal injection may have a minor influence on the ability to driveand use machines. Patients experiencing dizziness (see section 4.8) should avoid driving and usingmachines.
4.8 Undesirable effects
The safety data described in this section are from 127 patients from studies COAV101B12301,
COAV101B12302 and COAV101A12102 over a 52-week follow-up period (see section 5.1). Themost frequently reported adverse reactions following Itvisma administration were upper respiratorytract infection (41.7%), pyrexia (36.2%), vomiting (28.3%), headache (13.4%), and increased hepaticenzyme (9.4%). The most frequently reported serious adverse reactions were vomiting (2.4%),increased hepatic enzyme (1.6%), headache (1.6%) and pyrexia (1.6%). The adverse reactions reportedwere similar across studies.
Tabulated list of adverse reactionsThe adverse reactions identified with Itvisma in patients treated with intrathecal injection at therecommended dose are presented in Table 2. Adverse reactions are classified according to MedDRAsystem organ classification and frequency. Frequency categories are derived according to thefollowing conventions: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to< 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (frequency cannot beestimated from the available data). Within each frequency grouping, adverse reactions are presented inorder of decreasing seriousness.
Table 2 Tabulated list of adverse reactions to Itvisma
Adverse reactions by MedDRA SOC/PT and frequency
Infections and infestationsVery common Upper respiratory tract infectiona)
Blood and lymphatic system disordersCommon Thrombocytopeniab)
Nervous system disordersVery common Headachec)
Common Dizzinessc)
Common Peripheral sensory neuropathyd)
Common Hypoaesthesia
Common Paraesthesia
Gastrointestinal disordersVery common Vomiting
Hepatobiliary disordersCommon Hepatic enzyme increasede)
General disorders and administration site conditionsVery common Pyrexiaa) Upper respiratory tract infection includes upper respiratory tract infection, viral upper respiratory tractinfection, rhinitis, and oropharyngeal pain.b) Thrombocytopenia includes thrombocytopenia and platelet count decreased.c) Adverse reactions considered related to the lumbar puncture procedure.d) Peripheral sensory neuropathy includes peripheral sensory neuropathy and neuropathy peripheral.e) Hepatic enzyme increased includes hepatic enzyme increased, alanine aminotransferase increased,aspartate aminotransferase increased, hepatitis, hypertransaminasaemia and hepatic function abnormal.
Description of selected adverse reactionsPeripheral sensory neuropathy
In clinical studies, cases of peripheral sensory neuropathy (1.6%) have been observed withinapproximately three weeks following Itvisma administration. Patients presented with hypoaesthesiaand paraesthesia. These cases required prolonged symptom management and some symptoms had notfully resolved at the end of the study (see section 4.4).
Hepatic laboratory abnormalities
In clinical studies, all patients received prophylaxis with corticosteroids. The majority of patientsreceived the recommended immunomodulatory regimen with a median duration of approximately60 days (see section 4.2). AST or ALT elevations > 3 × ULN were observed in 4.7% of patientsfollowing Itvisma administration. Serum transaminase elevations resolved with prednisolone treatmentand patients recovered without clinical sequelae.
ImmunogenicityIn the clinical studies COAV101B12301 and COAV101B12302, following a one-time Itvismainjection, increases from baseline in serum anti-AAV9 antibody titres occurred in all patients. Medianserum anti-AAV9 antibody titres at 12 months following Itvisma injection were ˃ 1:800 000 in bothstudies. No clear association between post-administration anti-AAV9 antibody level and safetyfindings or loss of efficacy was seen in the studied population over the follow-up period of 12 monthspost-dose.
During the 12-month period following Itvisma injection in studies COAV101B12301 and
COAV101B12302, positive anti-SMN antibodies were observed in 5/75 (6.7%) and 2/27 (7.4%)
Itvisma-treated patients, respectively. No clear association can be made between a positive anti-SMNantibody response and safety or efficacy of Itvisma over the follow-up period of 12 months post-dose.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.
4.9 Overdose
No data from clinical studies are available regarding overdose of Itvisma. The dose of Itvisma is asingle, fixed dose and is administered only once, therefore overdose is considered unlikely.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other drugs for disorders of the musculo-skeletal system, ATC code:
M09AX09
Mechanism of actionOnasemnogene abeparvovec is a gene therapy designed to introduce a functional copy of the survivalmotor neuron gene (SMN1) in the transduced cells to address the monogenic root cause of spinalmuscular atrophy (SMA). By providing an alternative source of SMN protein expression in motorneurons, it is expected to promote the survival and function of transduced motor neurons.
Onasemnogene abeparvovec is a non-replicating recombinant AAV vector that utilises AAV9 capsidto deliver a stable, fully functional human SMN transgene. The SMN1 gene present in onasemnogeneabeparvovec is designed to reside as episomal DNA in the nucleus of transduced cells and is stablyexpressed in post-mitotic cells. The transgene is introduced to target cells as a self-complementarydouble-stranded molecule. Expression of the transgene is driven by a constitutive promoter(cytomegalovirus enhanced chicken-β-actin-hybrid), which results in continuous and sustained SMNexpression. Proof of the mechanism of action mainly derives from non-clinical studies.
Clinical efficacy and safetyCOAV101B12301 (STEER) phase III study in patients with SMA
This is a 52-week, randomised, double-blind, sham-controlled, multicentre study.
Efficacy was assessed in 126 patients with SMA aged 2 to < 18 years who were treatment-naïve andable to sit but never able to walk independently. Patients were randomised 3:2 and received Itvisma(1.2 × 1014 vg) by lumbar intrathecal injection (n=75) or sham procedure (n=51). Randomisation wasstratified by age and pre-treatment Hammersmith Functional Motor Scale - Expanded (HFMSE) scoreat screening. Patients with elevated (reference to ˃ 1:50) baseline serum anti-AAV9 antibody titrewere excluded.
The primary endpoint was the change from baseline in HFMSE total score at the end of follow-up,defined as the average of the week 48 and week 52 assessment, in the overall study population (2 to< 18 years age group) with Itvisma compared to sham. A secondary endpoint was the proportion ofpatients with at least a 3-point improvement from baseline in HFMSE total score at the end of follow-up. The HFMSE evaluates motor function in patients with SMA who have limited ambulation,comprising 33 graded items assessing movements ranging from sitting to using the stairs. Each item isscored from 0 to 2, with a maximum total score of 66. Higher scores indicate better motor function.
Another secondary endpoint was the change from baseline in Revised Upper Limb Module (RULM) atthe end of follow-up. The RULM is a SMA-specific assessment used to assess upper limb (proximaland distal) motor function. The RULM contains 19 graded items (18 scored from 0 to 2 and 1 scoredfrom 0 to 1), and there is a maximum achievable score of 37, with higher scores indicating greatermotor function.
The median age at screening was 4.54 years (range: 2.0 to 16.5 years) and the median reported age ofonset of clinical signs and symptoms of SMA was 11 months (range: 6 to 33 months). Patients’highest motor milestone ever achieved included sitting, standing with or without support, or walkingwith support. At baseline, the mean HFMSE score was 17.97 and 18.17 in the Itvisma-treated groupand sham-control group, respectively. The mean baseline RULM score was 16.52 in the Itvisma-treated group and 17.42 in the sham-control group. The baseline demographic characteristics werebalanced between the Itvisma and sham arms.
The primary endpoint analysis showed a statistically significant and clinically meaningfulimprovement in HFMSE scores from baseline at the end of follow-up in the Itvisma-treated groupcompared to the sham-control group (Table 3 and Figure 1).
Table 3 Primary endpoint in study COAV101B12301
Endpoint Itvisma-treated patients Sham-control patients (N=51)(N=75)
Mean HFMSE total score at 17.97 (10.110) 18.17 (9.756)baseline (SD)
Mean HFMSE total score at the 20.49 (11.356) 19.05 (10.132)end of follow-up1 (SD)
Change from baseline in total 2.39 (0.439) 0.51 (0.532)
HFMSE score2 at the end offollow-up in the overall studypopulation (2 to < 18 years agegroup)1, 2, 3, 4
Difference from sham 1.88
Estimate (95% CI) (0.51 - 3.25)
SD = Standard deviation1 The end of follow-up was defined as the average of the week 48 and week 52 assessment.2 Assessed using the Full Analysis Set (FAS) population, which included all participants who were dosedwith Itvisma or who underwent sham procedure3 Least squares (LS) mean (standard error of the mean [SEM])4 The Mixed Model Repeated Measure (MMRM) analysis with fixed effects included treatment, scheduledvisit, treatment by visit interaction, the strata, and the baseline HFMSE total score as covariate.
Figure 1 Change from baseline in HFMSE for patients aged 2 to ˂ 18 years in study
COAV101B12301
Itvisma Sham2.390.51
End of follow-
Baseline Week 12 Week 24 Week 36up
SSaammppllee s siizzee a att e eaacchh v viissitit
Sham
Itvisma
Note: Data represent LS mean ± SEM; intermediate time points are descriptive only and not controlled for multiplicity.
The change from baseline in RULM at the end of follow-up was assessed in the Itvisma-treated andsham-control groups. The least squares (LS) mean increase in RULM total score from baseline to theend of follow-up was 2.44 points in the Itvisma-treated group, and 0.92 points in the sham-controlgroup. The treatment difference of 1.52 points in favour of the Itvisma-treated group did not meetstatistical significance (95% CI: 0.34, 2.71) under an alpha level of 0.0025 per the pre-plannedmultiple testing strategy.
The percentage of patients with at least a 3-point improvement in total HFMSE score from baseline tothe end of follow-up was numerically higher in the Itvisma-treated group (39.2%) than the sham-control group (26.0%), although the difference did not meet statistical significance (odds ratio (OR):
2.03; 95% CI: 0.9, 4.57).
LS mean (± SEM) for change frombaseline in HFMSE score
Sixty-seven of the 75 patients from COAV101B12301 who received Itvisma continued to be followedfor an additional 3 months after the end of follow-up. Over the combined follow-up period of up to15 months following Itvisma administration, mean HFMSE scores continued to increase,demonstrating improved and sustained motor function.
COAV101B12302 (STRENGTH) phase III study in SMA patients previously treated with other SMA-modifying therapies
This is a phase III, open-label, single-arm, multicentre study of intrathecal administration of Itvisma(1.2 × 1014 vg) in 27 patients with SMA aged 2 to < 18 years (median age at screening: 7.0 years;range: 2.3 to 17.6 years) who discontinued previous SMA treatment (nusinersen n=21, risdiplam n=4,nusinersen and risdiplam [not concurrently] n=2). Prior to treatment with Itvisma, patients hadpreviously received nusinersen for a mean duration of 4.3 years (range: 1.86 to 6.18 years), andrisdiplam for a mean duration of 3.0 years (range: 0.39 to 6.28 years). All patients were able to sit butnever able to walk independently. Patients’ baseline motor function included sitting, standing with orwithout support and/or walking with support. Patients with elevated (reference to ˃ 1:50) baselineserum anti-AAV9 antibody titre were excluded.
At week 52, patients showed overall stabilisation in motor function as measured by HFMSE (n=21),with a mean (SD) change from baseline of 0.17 (2.88), and RULM (n=21), with a mean (SD) changefrom baseline of 0.29 (2.85). After adjusting for baseline age stratum, the adjusted mean (LS mean)change from baseline to week 52 in HFMSE and RULM total score was 1.05 and 0.59, respectively.
The majority of patients demonstrated maintenance of baseline motor milestones or higher motormilestones at week 52.
COAV101A12102 (STRONG) phase I/II study in patients with SMA
This is a phase I/II, open-label study in which Itvisma (1.2 × 1014 vg) was administered as a singleintrathecal injection in 25 patients from 6 months to < 5 years of age at the time of dosing. All patientswere treatment-naive and able to sit but never able to stand or walk independently at baseline. Patientswith elevated (reference to ˃ 1:50) baseline serum anti-AAV9 antibody titre were excluded. Patientswere stratified in two groups based on age at dosing (6 months to < 2 years of age (N=13); 2 to< 5 years of age (N=12)). The median age at dosing was 17.7 months (range: 7 to 23 months) in the6 months to < 2 years age group, and 33.7 months (range: 26 to 55 months) in the 2 to < 5 years agegroup. The median age of onset of clinical signs and symptoms of SMA was 8.0 months and8.5 months in the 6 months to < 2 years group and 2 to < 5 years group, respectively.
The primary efficacy endpoint for patients 2 to < 5 years of age was the change from baseline in
HFMSE at 12 months following Itvisma injection. The mean HFMSE score (SD) was 14.8 (9.98) atbaseline and 21.3 (11.94) at month 12. The primary analysis in this age group showed LS meanchange (95% CI) in HFMSE from baseline to month 12 of 6.0 (3.7, 8.3) points.
The primary efficacy endpoint for patients 6 months to < 2 years of age was the ability to stand alonefor at least 3 seconds (Bayley Scales of Infant and Toddler Development (Bayley-III) - Gross Motor(GM) Subtest Item #40), at any post-baseline visit up to 12 months following Itvisma injection. Theprimary endpoint was not met; 1 of the 13 patients demonstrated this milestone at month 12.
Exploratory analyses in patients 6 months to < 2 years of age show improvements from baseline ingross and fine motor skills, as measured by the Bayley-III Gross and Fine Motor Subtests. All13 patients showed improvement from baseline up to month 12 in gross and/or fine motor subtest totalscores, with a mean change (SD) from baseline of 6.7 (6.46) and 12.7 (3.71), respectively.
Furthermore, in a subset of patients who reached 2 years of age during the study and had at least sevenmonths post-baseline HFMSE data (n=6), all patients showed increases in HFMSE score ranging from1 to 14 points (mean ± SD change: 6.7 ± 4.72) from initial assessment of HFMSE to the end ofmonth 7. Efficacy has not been established in the 6 months to ˂ 2 years age-group.
Twelve of the 25 patients from COAV101A12102 were enrolled in a long-term study for up to7.2 years. As of 30 June 2025, the majority of patients maintained or further improved their motorfunction. Nine of the 12 patients received concomitant nusinersen or risdiplam treatment at some pointduring the long-term study. The reason for concomitant nusinersen or risdiplam is unknown and aconclusion on the treatment effect in those patients cannot be made.
5.2 Pharmacokinetic properties
Onasemnogene abeparvovec vector shedding studies, which assess the amount of vector DNAeliminated from the body through saliva, urine, faeces and nasal secretions, were performed followingintrathecal administration.
Vector DNA was detectable in shedding samples following intrathecal injection of onasemnogeneabeparvovec. Shedding (excretion) of onasemnogene abeparvovec was primarily via faeces. Themajority of the vector DNA (˃ 90%) is excreted within 2 weeks after dose administration. Peakshedding in faeces was estimated to be between 0.005% to 0.03% of total dose. The maximal sheddingconcentration in faeces was ~70-fold lower following intrathecal administration of 1.2 × 1014 vg in
COAV101B12301 compared with intravenous administration of 1.1 × 1014 vg/kg (studies AVXS-101-
CL-302 and AVXS-101-CL-303).
In subjects aged 6 months to ˂ 2 years, the CSF volume increases between 1.0- to 1.6-fold. Based onthis, onasemnogene abeparvovec exposure in the CSF in paediatric patients aged 6 months to ˂ 2 yearsmay be up to 1.6-fold higher compared to patients aged ≥ 2 years.
5.3 Preclinical safety data
Biodistribution
Following intrathecal administration in non-human primates, the vector was widely distributed withsubsequent expression of transgene mRNA. The highest vector DNA concentration was detected in theliver, followed by the dorsal root ganglia (DRG) and spinal cord, with the lowest concentration in thegonads. The highest concentration of transgene mRNA tended to occur in the heart, liver and muscle.
In mice dosed with onasemnogene abeparvovec via intravenous or intracerebroventricularadministration at PND1 (post-natal day 1), the viral vector was not detected in germline cells of malesand females at week 3, 8 or 24 post-dosing. In juvenile non-human primates treated with ascAAV9 viral vector, which is utilised in onasemnogene abeparvovec but here carrying greenfluorescent protein (GFP) or mCherry as transgene, this was shown to transduce oocytes of cyclingfemales 13-17 months of age, but not the seminiferous tubules or germ cells in sexually mature males,following intrathecal, intracisterna magna and intravenous administration.
In non-human primates, high pre-existing serum anti-AAV9 antibody titres (corresponding to humantitre values of up to approximately 1:25 000) were not shown to affect scAAV9 vector (utilised inonasemnogene abeparvovec) DNA distribution in the spinal cord following intrathecal administration.
General toxicityIn a 12-month toxicity study conducted in juvenile non-human primates, intrathecal administration ofa single dose of onasemnogene abeparvovec at doses of 1.20 × 1013, 3.0 × 1013, or6.0 × 1013 vg/animal, resulted at 6 weeks post-dosing in acute, minimal to moderate mononuclear cellinflammation and neuronal degeneration in the dorsal root ganglia (DRG) and trigeminal ganglia(TG), as well as axonal degeneration and/or gliosis in the spinal cord. At 12 months, these non-progressive findings resulted in partial to full resolution. These findings in non-human primates had nocorrelative clinical observations, therefore the clinical relevance in humans is unknown. Liver findingsin juvenile non-human primates, including elevated transaminase levels and single-cell necrosis ofhepatocytes, demonstrated complete reversibility at 12 months. A NOAEL (no observed adverse effectlevel) could not be identified because of the inflammation and degeneration in the CNS/DRG/TGalready at the lowest dose.
Genotoxicity and carcinogenicityGenotoxicity and carcinogenicity studies have not been conducted with onasemnogene abeparvovec.
Reproductive and developmental toxicityIn fertility and early embryonic development (FEED) studies conducted in mice, no adverse effects onmale or female fertility were observed with onasemnogene abeparvovec at doses of 1.1 × 1013 or1.1 × 1014 vg/kg administered intravenously.
In an embryofoetal development (EFD) study in mice, pregnant animals received an intravenous doseof either 1.1 × 1013 vg/kg or 1.1 × 1014 vg/kg of onasemnogene abeparvovec on GD6 (gestationalday 6). There was no evidence of maternal toxicity, embryofoetal toxicity, teratogenicity or reducedviability. There was no onasemnogene abeparvovec DNA detected in any foetal tissue at GD18,despite the presence of vector DNA in the placenta, ovaries and uterus.
The NOAEL for the EFD study and FEED studies is 1.1 × 1014 vg/kg, corresponding to at least 7 timesthe recommended clinical intrathecal dose based on body weight.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tromethamine
Magnesium chloride
Sodium chloride
Poloxamer 188
Hydrochloric acid (for pH adjustment)
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product should not be mixed with othermedicinal products.
Contact of the medicinal product with medical devices made of polyvinylchloride (PVC), bisphenol-A(BPA), bis(2-ethylhexyl) phthalate (DEHP) or latex must be avoided.
6.3 Shelf life
2 years
After thawing
Once thawed, the medicinal product should not be re-frozen.
May be stored refrigerated at 2 °C to 8 °C in the original carton for 14 days. The date of receipt shouldbe marked on the original carton before the medicinal product is stored in the refrigerator.
Once the dose is drawn into the syringe, it may be held at 2 °C to 8 °C for up to 24 hours, including a5-hour maximum time out-of-refrigeration allowance within the 24-hour period. The vector-containingsyringe should be discarded if not used within this time period.
6.4 Special precautions for storage
Store and transport frozen (≤ -60 °C).
Store in a refrigerator (2 °C - 8 °C) immediately upon receipt.
Store in the original carton.
For storage conditions after thawing of the medicinal product, see section 6.3.
6.5 Nature and contents of container
Itvisma is supplied in a single-dose clear vial (5 mL cyclic olefin polymer) with stopper (20 mmchlorobutyl rubber) and seal (aluminium, flip-off) with a coloured cap (plastic). Each vial has a fillvolume of 3 mL.
Each carton contains 1 vial.
6.6 Special precautions for disposal and other handling
Thawing
* Thaw Itvisma in the refrigerator (2 °C to 8 °C) for approximately 4 hours, or at roomtemperature (20 °C to 25 °C) for approximately 1 hour.
* Prior to intrathecal injection, Itvisma should be brought to room temperature.
* Itvisma is a clear to slightly opaque, colourless to faint white solution. Do not use this medicinalproduct if you notice any particles, cloudiness, or discolouration once the frozen product hasthawed and prior to administration.
* Do not shake.
* Once thawed, the medicinal product should not be re-frozen.
* After thawing, Itvisma should be given as soon as possible. Once the dose volume is drawn intothe syringe it may be held in the refrigerator (2 °C to 8 °C) for up to 24 hours, including a 5-hour maximum time out-of-refrigeration allowance within the 24-hour period. Discard thevector-containing syringe if not used within this time period.
Precautions to be taken before handling or administering the medicinal product* Itvisma should be handled aseptically under sterile conditions.
* This medicinal product contains genetically modified organisms (GMOs).
* Personal protective equipment (including gloves, safety goggles, laboratory coat and sleeves)should be worn while handling or administering Itvisma.
* The vial must be thawed before use. Do not use Itvisma unless thawed.
* Immediately prior to dosing, draw the content from the vial into the syringe, remove air fromthe syringe, confirm the dose volume of 3 mL in the syringe, cap the syringe and deliver to thepatient injection location.
* When assembling the injection, it must be ensured that the components’ surface in contact with
Itvisma solution consists of the compatible materials listed in Table 4. Device components mustbe indicated for intrathecal or neuraxial use.
Table 4 Component materials compatible with Itvisma
Component Material of construction18 to 19 G needle for withdrawal, maximum Stainless steel40 mm long5 to 10 mL syringea Polypropylene
Syringe capa Polypropylene, polyethylene or methacrylate-acrylonitrile-butadiene-styrene22 to 27 G spinal needle, maximum 156 mm Stainless steellonga Not to be manufactured with polyvinylchloride (PVC), bisphenol-A (BPA), bis(2-ethylhexyl) phthalate(DEHP) or latex
Precautions to be taken for the disposal and accidental exposure to the medicinal product
* All spills of Itvisma must be wiped with absorbent gauze pad and the spill area must bedisinfected using a bleach solution followed by alcohol wipes. All clean up materials must bedouble bagged and disposed of in accordance with local guidelines for handling of biologicalwaste.
* Any unused medicinal product or waste material should be disposed of in accordance with localguidelines on handling of biological waste.
* All materials that may have come in contact with Itvisma (e.g. vial, all materials used forinjection, including sterile drapes and needles) must be disposed of in accordance with localguidelines on handling of biological waste.
* Accidental exposure to Itvisma must be avoided. In the event of accidental exposure to skin, theaffected area must be thoroughly cleaned with soap and water for at least 15 minutes. In theevent of accidental exposure to eyes, the affected area must be thoroughly flushed with waterfor at least 15 minutes.
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines
Agency https://www.ema.europa.eu.