Onasemnogene Abeparvovec (Zolgensma)
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Spinal Muscular Atrophy (SMA) disorders are characterized by degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem. These diseases are classified as types 1 through 4 depending upon the age of onset and clinical course. The incidence of spinal muscular atrophy ranges from 4 to 10 per 100,000 live births, and the carrier frequency of disease-causing SMN1 mutations ranges from 1/90 to 1/50.
Zolgensma (onasemnogene abeparvovec) is an adeno-associated virus vector-based gene therapy indicated for the treatment of pediatric patient less than 2 years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival neuron 1 (SMN1) gene. Zolgensma (onasemnogene abeparvovec) is a one-time intravenously administered drug that delivers a copy of SMN in a self-complementary adeno-associated viral serotype 9 (scAAV9).
The efficacy of Zolgensma (onasemnogene abeparvovec) in pediatric patients less than 2 years of age with SMA with bi-allelic mutations in the SMN1 gene was evaluated in an open-label, single-arm clinical trial (ongoing) and an open-label, single-arm, ascending-dose clinical trial (completed). Patients experienced onset of clinical symptoms consistent with SMA before 6 months of age. All patients had genetically confirmed bi-allelic SMN1 gene deletions, 2 copies of the SMN2 gene, and absence of the c.859G>C modification in exon 7 of SMN2 gene (which predicts a milder phenotype). All patients had baseline anti-AAV9 antibody titers of ≤ 1:50, measured by ELISA.
In both trials, Zolgensma (onasemnogene abeparvovec) was delivered as a single-dose intravenous infusion. Efficacy was established on the basis of survival, and achievement of developmental motor milestones such as sitting without support. Survival was defined as time from birth to either death or permanent ventilation. Permanent ventilation was defined as requiring invasive ventilation (tracheostomy), or respiratory assistance for 16 or more hours per day (including noninvasive ventilatory support) continuously for 14 or more days in the absence of an acute reversible illness, excluding perioperative ventilation. Efficacy was also supported by assessments of ventilator use, nutritional support and scores on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND). CHOP-INTEND is an assessment of motor skills in patients with infantile-onset SMA
As of the March 2019 data cutoff, 19 patients were alive without permanent ventilation (i.e., event-free survival) and were continuing in the trial, while one patient died at age 7.8 months due to disease progression, and one patient withdrew from the study at age 11.9 months. The 19 surviving patients who were continuing in the trial ranged in age from 9.4 to 18.5 months. By the data cutoff, 13 of the 19 patients continuing in the trial reached 14 months of age without permanent ventilation, one of the study’s co-primary efficacy endpoints. In addition to survival, assessment of the other co-primary efficacy endpoint found that 10 of the 21 patients (47.6%) achieved the ability to sit without support for ≥ 30 seconds between 9.2 and 16.9 months of age (mean age was 12.1 months). Based on the natural history of the disease, patients who met the study entry criteria would not be expected to attain the ability to sit without support, and only approximately 25% of these patients would be expected to survive (i.e., being alive without permanent ventilation) beyond 14 months of age. In addition, 16 of the 19 patients had not required daily NIV use.
The completed clinical trial enrolled 15 patients (6 male and 9 female) with infantile-onset SMA, 3 in a low-dose cohort and 12 in a high-dose cohort. At the time of treatment, the mean age of patients in the low-dose cohort was 6.3 months (range 5.9 to 7.2 months), and 3.4 months (range 0.9 to 7.9 months) in the high-dose cohort. The dosage received by patients in the low-dose cohort was approximately one-third of the dosage received by patients in the high-dose cohort. By 24 months following Zolgensma infusion, one patient in the low-dose cohort met the endpoint of permanent ventilation; all 12 patients in the high-dose cohort were alive without permanent ventilation. None of the patients in the low-dose cohort were able to sit without support, or to stand or walk; in the high-dose cohort, 9 of the 12 patients (75.0%) were able to sit without support for ≥ 30 seconds, and 2 patients (16.7%) were able to stand and walk without assistance.
The most common adverse reactions (incidence ≥ 5%) were elevated aminotransferases and vomiting.
As per the FDA approved package insert Zolgensma (onasemnogene abeparvovec) carries a Black Box Warning for acute serious liver injury and elevated aminotransferases. Patients with pre-existing liver impairment maybe at a higher risk. Prior to infusion, access liver function of all patients by clinical examination and laboratory testing(e.g, hepatic aminotransferases[aspartate aminotransferase(AST) and alanine aminotransferase (ALT) ], total bilirubin and prothrombin time). Administer a systemic corticosteroid to all patients before and after Zolgensma (onasemnogene abeparvovec) infusion. Continue to monitor liver function for at least 3 months after infusion.
I. Zolgensma (onasemnogene abeparvovec) is medically necessary for the treatment of pediatric patients less than 9 months of age with spinal muscular atrophy (SMA) when all of the following criteria are met:
A. The patient has a confirmed genetic diagnosis of SMA type I as documented by the following:
B. Onset of SMA-associated signs and symptoms before 6 months of age AND
[INFORMATIONAL NOTE: Based on the inclusion criteria of the two clinical trials that are listed in the Zolgensma FDA package labeling, patients that received the drug were limited to up to 6 months of age to a maximum of 9 months of age or younger. Inclusion criteria for the START trial (NCT02122952) stated patients were 6 or 9 months of age and younger on day of infusion. Inclusion criteria for the STR1VE trial (NCT03306277) stated patients must have been <6 months of age at time of infusion.]
C. Documentation of anti-adeno-associated virus serotype 9 antibody titer ≤1:50 AND
II. When Zolgensma (onasemnogene abeparvovec) is considered medically necessary, therapy will be approved once per lifetime based on FDA-approved labeling:
D. Patient does not have advanced SMA (e.g., complete paralysis of limbs or permanent ventilator dependence) AND
E. Documentation of baseline platelet counts, troponin-I, AST/ALT/bilirubin levels/prothrombin time AND
F. Patient has not previously received a gene therapy for SMA or is not concurrently enrolled in a clinical trial for any experimental therapy for SMA AND
G. Patient has not previously received Spinraza (nusinersen) AND
[INFORMATIONAL NOTE: All patients enrolled in clinical trials had not received any therapy (including Spinraza) prior to using Zolgensma. 3 out of 10 patients in the long-term follow up study did use Spinraza at least 2 years after Zolgensma, however no clinical benefit was seen these patients compared to those that used Zolgensma alone.]
H. Baseline documentation of at least one of the following:
• Patient’s weight in those who are without gastrostomy tube
• Motor function/milestones, as shown in the Hammersmith Infant Neurologic Exam (HINE) Hammersmith Functional Motor Scale Expanded (HFMSE), 6-minute walk test (6MWT), upper limb nodule (ULM), CHOP-INTEND
• Respiratory function test such as forced vital capacity
• Patient has exacerbations requiring hospitalization and/or antibiotic therapy for respiratory infection within the prior year
[INFORMATIONAL NOTE: The HINE Exam evaluates seven different areas of motor milestone development, with a maximum score between 2-4 points for each, depending on the milestone, and a total maximum score of 26. A treatment responder was defined as any patient with at least a 2-point increase (or maximal score of 4) an ability to kick (consistent with improvement by at least 2 milestones), or at least a 1-point increase in the motor milestones of head control, rolling, sitting, crawling, standing or walking (consistent with improvement by at least 1 milestone. To be classified as a responder, patients needed to exhibit improvement in more categories of motor milestones; 6MWT an objective evaluation of functional exercise capacity that measures the maximum distance a person can walk in 6 minutes over a 25-meter linear course; ULM is an outcome measure specifically developed to assess upper limb functional abilities in patients with SMA, including young children and patients with severe contractures in the lower limbs, in whom the possibility to detect functional changes, such as rolling or long sitting, is limited; CHOP-INTEND measures motor function via 16 different items, which capture neck, trunk, proximal and distal limb strength. Scored from 0 (least function) to 4 (most function) for each of the 16 items.]
a. Dose volume is calculated using the upper limit of the patient weight range for pediatric patients less than 2 years of age between 2.6 kg and 13.5 kg
A. 1.1 x 10^14 vector genomes per kilogram (vg/kg) of body weight as a one-time infusion
As per the FDA package insert: See table 1 - Dosing Table
Table 1: Dosing
|Patient Weight Range (kg)||Dose Volume (mL)|
|2.6 - 3.0||16.5|
|3.1 - 3.5||19.3|
|3.6 - 4.0||22.0|
|4.1 - 4.5||24.8|
|4.6 - 5.0||27.5|
|5.1 - 5.5||30.3|
|5.6 - 6.0||33.0|
|6.1 - 6.5||35.8|
|6.6 - 7.0||38.5|
|7.1 - 7.5||41.3|
|7.6 - 8.0||44.0|
|8.1 - 8.5||46.8|
|8.6 - 9.0||49.5|
|9.1 - 9.6||52.3|
|9.6 - 10.0||55.0|
|10.1 - 10.5||57.8|
|10.6 - 11.0||60.5|
|11.1 - 11.5||63.3|
|11.6 - 12.0||66.0|
|12.1 - 12.5||68.8|
|12.6 - 13.0||71.5|
|13.1 - 13.5||74.3|
b. Dose volume for pediatric patients less than 2 years of age weighing equal to or greater than 13.6 kg will require a combination of ZOLGENSMA kits
[INFORMATIONAL NOTE: The safety and efficacy of repeat administration of Zolgensma (onasemnogene abeparvovec) have not been evaluated.
As per the FDA approved package insert, monitor liver function by clinical examination and by laboratory testing on a regular basis. One day prior to Zolgensma infusion, begin administration of systemic corticosteroids equivalent to oral prednisolone at 1 milligram per kilogram of body weight per day (mg/kg/day) for a total of 30 days. At the end of the 30-day period of systemic corticosteroid treatment, check liver status clinically and by assessing ALT, AST, total bilirubin, and prothrombin time. For patients with unremarkable findings (normal clinical exam, total bilirubin, and prothrombin time, and ALT and AST levels below 2 × upper limit of normal (ULN)), taper the corticosteroid dose over the next 28 days. If liver function abnormalities persist, continue systemic corticosteroids (equivalent to oral prednisolone at 1 mg/kg/day) until AST and ALT values are both below 2 × ULN and all other assessments return to normal range, and then taper the corticosteroid dose over the next 28 days.]
III. Other uses of Zolgensma (onasemnogene abeparvovec) are considered investigational, including but not limited to, other types of SMA besides SMA type 1, asymptomatic SMA, etc.
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Onasemnogene Abeparvovec (Zolgensma)
Zolgensma (Onasemnogene Abeparvovec)
1. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy N Engl J Med 2017;377:1713-22. DOI: 10.1056/NEJMoa1706198
2. Zolgensma [package insert]. Bannockburn, IL: AveXis, Inc.; May 2019.
3. Zolgensma. Clinicaltrial.gov. Accessed on 5/22/19 . Available at: https://clinicaltrials.gov/ct2/show/NCT02122952
4. Zolgensma. Clinicaltrial.gov. Accessed on 5/22/19 . Available at: https://clinicaltrials.gov/ct2/show/NCT03306277
5. Spinal Muscular Atrophy 1 | Genetic And Rare Diseases Information Center (GARD). Rarediseases.Info.Nih.Gov, 2019, https://rarediseases.info.nih.gov/diseases/7883/spinal-muscular-atrophy-1.
6. Arnold, W David et al. “Spinal muscular atrophy: diagnosis and management in a new therapeutic era.” Muscle & nerve vol. 51,2 (2015): 157-67. doi:10.1002/mus.24497
7. Prior TW, Finanger E. Spinal Muscular Atrophy. 2000 Feb 24 [Updated 2016 Dec 22]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1352/
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