Summary Basis of Decision for Spinraza
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Spinraza is located below.
Recent Activity for Spinraza
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Post-Authorization Activity Table (PAAT) for Spinraza
Updated:
The following table describes post-authorization activity for Spinraza, a product which contains the medicinal ingredient nusinersen (supplied as nusinersen sodium). For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
Drug Identification Number (DIN):
- DIN 02465663 - 2.4 mg/mL, nusinersen (supplied as nusinersen sodium), solution, intrathecal
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| NC # 220460 | 2018-09-25 | Issued NOL2018-12-31 | Submission filed as a Level II (90 day) Notifiable Change to update the PM to reflect revisions in the company core data sheet. As a result of the NC, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued. |
| SNDS # 209005 | 2017-08-31 | Issued NOC2018-08-14 | Submission filed as a Level I - Supplement to update the PM. The sponsor provided final analyses from Studies CS3B, CS4 and CS12. As a result of the SNDS, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM. The data were reviewed and considered acceptable, and an NOC was issued. |
| NC # 211749 | 2017-11-30 | Issued NOL2018-02-16 | Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with new safety information. As a result of the NC, additions were made to the Adverse Reactions section of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued. |
| Drug product (DIN # 02465663) market notification | Not applicable | Date of first sale:2017-08-29 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 200070 | 2016-11-10 | Issued NOC2017-06-29 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Spinraza
Date SBD issued: 2017-08-15
The following information relates to the new drug submission for Spinraza.
Nusinersen (supplied as nusinersen sodium), 2.4 mg/mL, solution, intrathecal
Drug Identification Number (DIN):
- 02465663
Biogen Canada Inc.orporated
New Drug Submission Control Number: 200070
On June 29, 2017, Health Canada issued a Notice of Compliance to Biogen Canada Incorporated for the drug product Spinraza.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and effectiveness) information submitted. Based on Health Canada's review, the benefit-harm-uncertainty profile of Spinraza is acceptable for the treatment of 5q spinal muscular atrophy
1 What was approved?
Spinraza, an antisense oligonucleotide, was authorized for the treatment of 5q spinal muscular atrophy (SMA).
The efficacy and safety data supporting the use of Spinraza for the treatment of SMA were from:
- a randomized, controlled trial and an ongoing open-label clinical trial that included patients with infantile-onset SMA;
- completed and ongoing open-label clinical trials in children with later-onset SMA; and
- an ongoing open-label clinical trial in presymptomatic infants with genetically diagnosed SMA.
Knowledge of the disease natural history and the use of management strategies that assist the patient in coping with the manifestations of SMA, which may include decline in motor function, serious respiratory complications and feeding difficulties remain necessary for the overall management of the disease. Treatment with Spinraza should only be initiated by healthcare professionals who are experienced in the management of SMA.
There are limited data in patients over 18 years of age. Spinraza has been studied in patients ranging in age from newborn to 19 years. There are no data from patients over the age of 65.
Spinraza is contraindicated in patients with known or suspected hypersensitivity to nusinersen or to any of the ingredients in the formulation or component of the container.
Spinraza was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Spinraza (2.4 mg/mL nusinersen as nusinersen sodium) is presented as a solution for intrathecal injection. In addition to the medicinal ingredient, the solution contains calcium chloride dihydrate, disodium phosphate, magnesium chloride hexahydrate, potassium chloride, sodium chloride, sodium dihydrogen phosphate dihydrate, and water for injection. Sodium hydroxide and hydrochloric acid may be used for pH adjustment.
Spinraza is administered intrathecally via lumbar puncture.
For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Spinraza Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Spinraza approved?
Health Canada considers that the benefit-harm-uncertainty profile of Spinraza is acceptable for the treatment of 5q spinal muscular atrophy (SMA).
Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease characterized by progressive degeneration of motor neurons, which results in atrophy of the voluntary muscles of the limbs and trunk, impaired feeding, and respiratory insufficiency. Although SMA is a rare disease, with a global incidence of 8.5 to 10.3 per 100,000 live births, it is the most common genetic cause of infant mortality and a major cause of childhood morbidity. There are no approved therapies for the treatment of SMA. Current medical care is supportive and focuses on respiratory, nutritional and musculoskeletal support. Thus, the need for an effective treatment of SMA remains largely unmet.
Spinal muscular atrophy can have varying degrees of severity and age of onset, based on the underlying genetic mutation present. More than 90% of the SMA cases are attributed to mutations in chromosomal region 5q11-q13, all of which lead to loss of function of the survival motor neuron 1 (SMN1) gene. The loss of the SMN1 gene function results in reduced levels of the survival motor neuron (SMN) protein, which causes dysfunction, and eventually, death of motor neurons.
In humans, the SMN1 gene has a nearly identical copy, SMN2. Although both genes encode proteins with identical amino acid sequences, SMN2 differs from SMN1 by 11 nucleotides. One of the 11 base differences, a cytosine to thymine substitution, occurs in exon 7 of the SMN2 gene, resulting in an alternative splicing pattern that favours skipping of exon 7. Eighty to 90% of the transcripts produced from the SMN2 gene lack exon 7, resulting in a truncated protein product that is defective and unstable.
Nusinersen, the medicinal ingredient in Spinraza, is a synthetic antisense oligonucleotide specifically designed to treat SMA. Nusinersen binds to a specific sequence in the intron downstream of exon 7 of the SMN2 gene transcript, promoting the increase in inclusion of exon 7 in the SMN2 gene transcript. The result is increased production of a full-length SMN protein, equivalent to the SMN protein produced by the SMN1 gene. Increasing the amount of a full-length transcript from the SMN2 gene is predicted to result in an increase in SMN protein in patients with SMA, which in turn, is expected to improve patient outcomes. Humans have a variable number of copies of the SMN2 gene (0 to 8 copies). The number of the SMN2 gene copies is an important predictor of SMA disease severity, and patients with more copies generally have a less severe form of the disease.
The market authorization of Spinraza was based on the efficacy and safety data from a planned interim analysis of a single pivotal Phase III, randomized, double-blind, sham-procedure controlled clinical trial that included patients with infantile-onset SMA (Type 1 SMA), 30 to 262 days old at treatment onset. Additionally, supportive efficacy and safety data were obtained from open-label clinical trials conducted in patients with infantile-onset SMA (1 study, ongoing), patients with later-onset SMA (4 studies: 3 completed, 1 ongoing) and patients with presymptomatic, genetically diagnosed SMA (1 study, ongoing). In total, 173 patients were treated with Spinraza in these clinical trials (as of the time of this new drug submission). The two clinical trials conducted in patients with infantile-onset SMA included approximately 100 patients treated with Spinraza.
The primary endpoint of the pivotal trial was the proportion of patients who could be considered motor milestone responders based on the protocol-specified level of achievement of developmental motor milestones assessed by the Hammersmith Infant Neurological Examination. A statistically significantly greater proportion of patients in the Spinraza group (41%) compared to the sham-control group (0%) met the definition of a motor milestone responder (p<0.0001). Patients treated with Spinraza in the pivotal study generally achieved more advanced motor milestones and sustained these abilities, whereas the motor milestones achieved by patients who received the sham-procedure control were less advanced and less likely to be sustained. The largest proportion of patients who met the definition of a motor milestone responder in both the pivotal and the open-label study in infantile-onset SMA had improvements in head control, rolling, and sitting. Several patients also achieved touching toes, a level of standing, and two patients were able to walk. Clinically meaningful improvements were also observed in both studies on assessments of motor function. For patients with Type 1 SMA, who by definition, never achieve independent sitting, the observed improvements in motor milestones and motor function (as measured by other assessment scales) were inconsistent with the natural history of Type 1 SMA and beyond what has been observed in patients with Type 1 SMA who received supportive care in natural history studies.
Although there were clinically meaningful improvements in motor milestones, motor function and event-free survival, many of the infants who received Spinraza in both the pivotal and the open-label study still developed a need for some level of respiratory support while on treatment, albeit less than what was needed in the sham-procedure control group in the pivotal study. In the pivotal study, there were no differences between the Spinraza group and the sham-procedure control group in the annualized rates of serious respiratory events or hospitalizations. This suggests that for many patients with infantile-onset SMA, the need for continued use or initiation of supportive treatments to manage the manifestations of SMA (e.g., orthopedic support, surgeries, respiratory support, and nutritional support) may not be eliminated during treatment with Spinraza.
In an ongoing open-label clinical trial, infants (8 to 42 days old at first dose) with presymptomatic, genetically diagnosed SMA, who are expected to develop Type 1, Type 2 or Type 3 SMA, are being treated with Spinraza. At the interim analysis, patients in this study were achieving developmental motor milestones and gains in motor function at ages that are expected for normal healthy infants, when otherwise most of these patients would be expected to manifest symptoms of SMA.
In four open-label clinical trials in which children (2 to 15 years old at first dose) with later-onset SMA were treated with Spinraza, there were clinically meaningful improvements in motor function, including upper body strength in non-ambulatory patients and walking ability in ambulatory patients.
Spinraza was a well-tolerated treatment across all age groups studied and across the different SMA subtypes. The non-serious and serious treatment-emergent adverse events that occurred in the clinical trials were largely related to the known complications of SMA or the lumbar puncture procedure. The only reported deaths in clinical trials occurred in the two studies with patients with infantile-onset SMA due to serious respiratory events or complications from respiratory infections. There were no patients who discontinued treatment or were withdrawn from any of the clinical trials due to treatment-emergent adverse events.
Safety concerns associated with the use of Spinraza included transient mild reductions in platelet count, transient mild elevated urine protein and rashes (red macular lesions), all of which may be potential indicators of toxicities (thrombocytopenia, nephrotoxicity, vasculitis) that have occurred to varying degrees when other antisense oligonucleotides in the same class as Spinraza were administered intravenously or subcutaneously in non-clinical and clinical studies. Therefore, these effects are not specific to the sequence of the antisense oligonucleotide, but rather are class-related effects.
In the pivotal clinical trial in patients with infantile-onset SMA, the reductions in platelet count, elevated urine protein and rashes were observed more frequently in patients who received Spinraza than in the sham-procedure control group. None of the occurrences of platelet count reductions or elevated urine protein were considered treatment-emergent adverse events and none were associated with relevant clinical symptoms or changes in other relevant clinical laboratory parameters. The rashes appeared to resolve despite continued treatment, although recurred in one of the two patients. The clinical significance of the observed platelet count reductions, elevated urine protein and rashes is not known, because these effects were not seen consistently across studies (platelet count reductions, elevated urine protein were seen in some patients in open-label studies). Although the intrathecal route of Spinraza administration could potentially mitigate severe toxic effects, there is nonetheless some systemic exposure with Spinraza, and its half-life is long. In addition, similar to other antisense oligonucleotides, the kidney is a target organ where the highest concentrations of Spinraza are observed, i.e., higher than in the central nervous system (CNS) tissues. In view of all of these factors and the limited characterization of long-term safety, the relationship between Spinraza and these identified safety concerns remains uncertain. Therefore, these safety concerns and respective monitoring recommendations (platelets, coagulation, and urine protein) have been included in the Warnings and Precautions section of the Spinraza Product Monograph.
An additional safety concern with Spinraza relates to the potential neurotoxicity observed in repeat-dose toxicity studies in juvenile monkeys that showed time and concentration-dependent hippocampal histopathology (neuronal vacuolation and neuronal and glial cell necrosis/cellular debris). One of the studies also suggested there were potential learning deficits in the animals. Because the concentrations at which the observed hippocampal histopathology and potential learning deficits occurred were within the recommended clinical dose range and the long-term safety of Spinraza has not been fully elucidated, the clinical relevance of the hippocampal histopathology and potential learning deficits in monkeys is not known. These findings have been described in the Warnings and Precautions section of the Spinraza Product Monograph.
There has been a post-marketing report of meningitis associated with the lumbar puncture procedure used for Spinraza administration.
As part of the marketing authorization for Spinraza, Health Canada requested that the sponsor agree to several commitments to be addressed post-market. Commitments include (but are not limited to) providing final reports of ongoing clinical studies and long-term safety data (see What follow-up measures will the company take?).
A Risk Management Plan (RMP) for Spinraza was submitted by Biogen Canada Incorporated to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
A Look-alike Sound-alike brand name assessment was performed and the proposed name Spinraza was accepted.
Overall, Spinraza has been shown to have an acceptable benefit-harm-uncertainty profile based on non-clinical and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Spinraza Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Spinraza?
The New Drug Submission for Spinraza was initially filed under the Notice of Compliance with Conditions (NOC/c) Guidance. However, upon completion of the review, Health Canada determined that the submitted clinical data could support a recommendation for a Notice of Compliance (NOC) for Spinraza for the treatment of 5q spinal muscular atrophy.
Submission Milestones: Spinraza
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2016-07-26 |
| Submission filed: | 2016-11-10 |
| Screening | |
| Screening Acceptance Letter issued: | 2016-12-12 |
| Review | |
| Quality Evaluation complete: | 2017-06-27 |
| Clinical Evaluation complete: | 2017-06-28 |
| Review of Risk Management Plan complete: | 2017-06-14 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2017-06-27 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2017-06-29 |
The Canadian regulatory decision on the quality, non-clinical, and clinical review of Spinraza was based on a critical assessment of the data package submitted to Health Canada. Some foreign review material completed by the European Medicines Agency (EMA) was also submitted as part of this New Drug Submission and used as an added reference.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
As part of the marketing authorization for Spinraza, Health Canada requested and the sponsor agreed to several commitments to be addressed post-market. In addition to requirements outlined in the Food and Drugs Act and Regulations, commitments include (but are not limited to) submitting the following clinical study reports, as soon as they become available:
- Final clinical study reports for the studies in patients with infantile-onset or later-onset SMA that were ongoing at the time of this new drug submission, and the final analysis results from the pivotal study in patients with infantile-onset SMA.
- Final reports for all studies that are post-market requirements in the United States, i.e., 2-year carcinogenicity study in one rodent species; prenatal and postnatal development study in rodents; study to assess development of antibodies to double-stranded deoxyribonucleic acid (DNA) in nusinersen-treated patients.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
Nusinersen, the medicinal ingredient in Spinraza, is an antisense oligonucleotide specifically designed to treat spinal muscular atrophy (SMA), an autosomal recessive, progressive neuromuscular disease caused by mutations in the chromosome 5q. These mutations lead to loss of function of the survival motor neuron 1 (SMN1) gene, resulting in deficiency of SMN protein. The SMN2 gene also produces SMN protein but at low levels. In patients with SMA, fewer SMN2 gene copies are associated with earlier age of onset and increased severity of symptoms.
Nusinersen binds to a specific site in the SMN2 pre-messenger ribonucleic acid (pre-mRNA) to increase the proportion of exon 7 inclusion in the SMN2 messenger ribonucleic acid (mRNA) transcripts made, which can be translated into the functional full-length SMN protein.
Single- and multiple-dose studies were conducted in pediatric patients diagnosed with SMA to evaluate the pharmacokinetics of nusinersen following administration by intrathecal injection. The recommended dose for nusinersen is 12 mg/injection, administered intrathecally via lumbar injection as four loading doses over a period of approximately two months, followed by maintenance doses administered at four-month intervals. The 12 mg dose has been studied in all age groups included in the clinical development program. Initially, the clinical development program included clinical trials conducted in patients with later-onset SMA and used longer intervals between doses. The recommended dosing regimen has been studied and well-tolerated in clinical trials with patients with infantile-onset SMA and very young infants with presymptomatic genetically diagnosed SMA. The recommended dosing regimen has been shown to result in achieving steady state earlier in treatment, which appears to be important for the therapeutic effects. Based on a population pharmacokinetic study, this dosing regimen is expected to be well-tolerated across all age groups.
For further details, please refer to the Spinraza Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Spinraza was demonstrated primarily on the basis of data from a planned interim analysis of a single pivotal Phase III, randomized, double-blind, sham-procedure controlled clinical trial in patients with infantile-onset SMA (Type 1 SMA). In addition, supportive efficacy data were derived from open-label clinical trials conducted in patients with infantile-onset SMA (one study, ongoing), patients with later-onset SMA (four studies: three completed, one ongoing) and patients with presymptomatic genetically diagnosed SMA (one study, ongoing).
Across the clinical trials, there were a total of 173 SMA patients treated with Spinraza at the time of the new drug submission. Of those, the two clinical trials in patients with infantile-onset SMA included approximately 100 patients treated with Spinraza.
At the interim analysis of the pivotal study, the primary endpoint assessed was the proportion of patients with infantile-onset SMA who could be considered motor milestone responders based on the protocol-specified level of achievement of developmental motor milestones evaluated by the Hammersmith Infant Neurological Examination. The interim analysis showed that a statistically significantly greater proportion of patients in the Spinraza group met the definition of a motor milestone responder as compared to the sham-procedure control group (41% vs. 0%; p<0.0001). Among the patients who met the definition of a motor milestone responder, the largest proportion had improvements in head control, sitting and rolling, and their achieved motor milestones were generally sustained with continued treatment. Any motor milestones achieved by patients who received the sham-procedure control were less advanced and less likely to be sustained.
The pivotal study findings were supported by interim data from an ongoing open-label clinical trial with a longer treatment and observation period, also conducted in patients with infantile-onset SMA. Similar to the pivotal study results, the largest proportion of patients who met the definition of a motor milestone responder had improvements in head control, rolling, sitting and touching toes. Several patients also achieved a level of standing and two patients were able to walk.
In addition, in both studies, patients treated with Spinraza showed clinically meaningful improvements in other assessments of motor function for infants with SMA. Event-free survival was also improved in patients treated with Spinraza in these studies. In the pivotal study, there was a 29% reduction in the risk of death or the need for permanent ventilation or tracheostomy. Also, the average total daily time on ventilation support was shown to be shorter in patients who received Spinraza compared to the patients who had sham procedures. In the open-label study including Type 1 SMA infants, the 15 patients who were continuing in the study at the time of the data cut-off were all over 2 years of age, which exceeds the life expectancy (below 2 years of age) for this subtype of SMA patients.
In the pivotal study, there were no differences between the Spinraza and sham-procedure control groups in the annualized rates of serious respiratory events or hospitalizations. This suggests that for many patients with infantile-onset SMA, the need for continued use or initiation of supportive treatments to manage the manifestations of SMA (e.g., respiratory support, orthopedic support, surgeries, and nutritional support) may not be eliminated during treatment with Spinraza.
Six out of 10 patients included in the interim analysis of an open-label study that included presymptomatic infants (8 to 42 days old at treatment onset) who were genetically diagnosed with SMA and treated with Spinraza during the presymptomatic period, had not developed clinically manifested SMA when these patients were approximately 6 months old. Four of these patients had two copies of the SMN2 gene and would otherwise be expected to develop Type 1 SMA and have symptoms by the age of 6 months. These infants were achieving motor milestones and had increased motor function that was consistent with normal development.
Patients with later-onset (Type 2 or Type 3) SMA (2 to 15 years old at treatment onset) treated with Spinraza in open-label clinical trials showed clinically meaningful improvements in motor function, upper limb strength and ambulation that were maintained over time. The observed sustained improvements or maintenance of motor function in the later-onset SMA patients treated with Spinraza were inconsistent with the declines that are typically observed in patients with Type 2 and Type 3 SMA.
Overall, the clinical trials provided evidence of clinically meaningful treatment effects with Spinraza across all age ranges (from newborn to 15 years of age at treatment onset) and across the SMA subtypes that were included in the studies (Type 1, Type 2, Type 3, and presymptomatic genetically diagnosed SMA).
Indication
The New Drug Submission for Spinraza was filed by the sponsor with the following indication:
- Spinraza is indicated for the treatment of spinal muscular atrophy (SMA).
To ensure safe and effective use of the product, Health Canada approved the following indication:
- Spinraza (nusinersen) is indicated for the treatment of 5q spinal muscular atrophy (SMA).
The efficacy and safety data supporting the use of Spinraza for the treatment of SMA were from:- a randomized, controlled trial and an ongoing open-label clinical trial that included patients with infantile-onset SMA;
- completed and ongoing open-label clinical trials in children with later-onset SMA; and
- an ongoing open-label clinical trial in presymptomatic infants with genetically diagnosed SMA.
For more information, refer to the Spinraza Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The safety of Spinraza in patients with SMA was evaluated in seven clinical trials (described in the Clinical Efficacy section). A total of 173 SMA patients were exposed to Spinraza for a total duration of 6 to 1,536 days (median duration 324 days).
The non-serious and serious treatment-emergent adverse events that occurred in the clinical trials were largely related to the known complications of SMA (e.g., respiratory failure, respiratory distress, aspiration, respiratory infections, musculoskeletal disorders) and/or the lumbar puncture procedure (e.g., post-lumbar puncture syndrome, headache, back pain, vomiting). The only reported deaths in clinical trials occurred in the two studies with patients with infantile-onset SMA and were secondary to serious respiratory events or complications from respiratory infections. There were no patients who discontinued treatment or were withdrawn from any of the clinical trials due to treatment-emergent adverse events.
Mild transient platelet count reductions, mild elevations in urine protein, and skin rashes were observed in clinical trials with Spinraza. These findings are considered safety concerns associated with the use of Spinraza because they may be potential indicators of toxicities (thrombocytopenia, nephrotoxicity, and vasculitis) that have been described with the intravenous or subcutaneous administration of other antisense oligonucleotides in the same class.
In the pivotal trial, mild transient platelet count reductions were reported at a higher frequency in patients treated with Spinraza (11%) compared to the sham-procedure control group (0%). None of the patients had a platelet count lower than 50,000 cells/microliter or a sustained low count, and there were no bleeding or coagulation adverse events. Transient mild elevations in urine protein were also reported more frequently in Spinraza-treated patients (33%) compared to the sham-procedure control group (20%). There were no relevant changes in other renal function clinical laboratory parameters and no adverse events suggesting nephrotoxicity were reported.
Across the open-label clinical trials, platelet count reductions and elevated urine protein levels were not seen consistently but were observed in some patients.
Non-clinical and clinical studies with other 2'-O-2-methoxyethyl phosphorothioate antisense oligonucleotides have shown varying degrees of thrombocytopenia and nephrotoxicity when administered intravenously or subcutaneously. Similar to other antisense oligonucleotides, the kidney is a target organ where Spinraza accumulates at higher concentrations than other tissues, including central nervous system (CNS) tissues. In animal toxicology studies, the localization of other antisense oligonucleotides in renal proximal tubules has been shown to be associated with concentration-dependent histopathological changes in tubular epithelial cells. Consistent with the Spinraza non-clinical data and published findings for other antisense oligonucleotides, the autopsy/pathology reports for Spinraza-treated infants who died during the open-label clinical trial indicated that Spinraza concentrations were high in the proximal renal tubules but no histopathology was noted.
Rashes that consisted of painless red, macular lesions (ulcerative with acral distribution in one patient) were reported in two patients treated with Spinraza in the pivotal trial. In both cases, the rashes resolved over several months while Spinraza treatment continued, but recurred in one patient. The rash adverse events were not considered to be cases of vasculitis, but their appearance and distribution showed some similarity to rare published case reports of vasculitis in patients with SMA (thought to be related to the disease). Vasculitis has also been described in non-clinical studies with other antisense oligonucleotides. None of these safety findings presented serious safety concerns in the clinical trials. The intrathecal route of administration of Spinraza may help to mitigate any potential toxic effects of Spinraza in peripheral tissues that may be related to known toxicological effects observed with intravenous or subcutaneous administration of some other drugs in this class of antisense oligonucleotides. However, in the context of limited characterization of the long-term safety of Spinraza, the clinical significance of these observations is uncertain at this time.
Across seven clinical studies in which the immunogenic response to Spinraza, i.e., the occurrence of anti-drug antibodies (ADAs) in plasma was evaluated, four patients had a positive ADA response. Responses in three of four patients were transient, and one patient was considered to have a pre-existing persistent response. Consistent with what was observed in non-clinical studies, the transient positive ADA responses did not have an effect on Spinraza plasma concentrations and did not appear to affect efficacy. However, the small number of positive samples precluded a formal analysis of the effect of immunogenicity on efficacy.
There has been a post-marketing report of meningitis associated with the lumbar puncture procedure used for Spinraza administration.
Appropriate warnings and precautions are in place in the approved Spinraza Product Monograph to address the identified safety concerns.
For more information, refer to the Spinraza Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Spinal muscular atrophy (SMA) is caused by the loss of function of the SMN1 gene on chromosome 5q, which results in reduced levels of the SMN protein and, consequently, leads to dysfunction and death of motor neurons. In humans, the SMN1 gene has a nearly identical copy, SMN2. Nusinersen, the medicinal ingredient in Spinraza, is designed to target the SMN2 gene in order to increase the levels of the SMN protein to improve functioning in SMA patients.
As humans are the only species known to have the SMN2 gene, the non-clinical pharmacological effects of nusinersen could only be studied in genetically modified animal models of SMA or human cells. In general, genetic engineering techniques were used to remove the endogenous mouse gene and add various numbers of copies of the human SMN2 gene. The mouse models of SMA with more copies of the human SMN2 gene typically exhibit milder SMA phenotypes than those with fewer copies. The pharmacological properties of nusinersen were assessed in multiple transgenic mouse models of SMA with varying degrees of phenotypic severity.
For pharmacokinetic/pharmacodynamic relationships, a mild SMA model expressing four copies of the human SMN2 gene was used in order to minimize potential complications associated with the rapid deterioration and morbidity found in the severe SMA models. Publications from peer-reviewed journals provided results from studies using mouse models of SMA with more severe phenotypes, which were used to assess the efficacy of nusinersen. The results from these studies showed that nusinersen increased survival, motor function, and body weight gain in transgenic mice representative of a severe SMA model. Survival was extended in a dose-dependent manner and it was associated with improved histology in neuromuscular junctions and skeletal muscle tissue.
Given that common laboratory animal species (mice, rats, dogs, macaques) used in toxicity studies lack the SMN2 gene, it was not possible to evaluate the toxicity of nusinersen in a pharmacologically responsive species. However, since the consequence of modulating splicing of the SMN2 transcript is increased production of the full-length SMN protein, which is already produced in healthy subjects and at insufficient levels in SMA patients, the on-target safety risk was considered by the sponsor to be minimal. Thus, the toxicity assessment was focused on non-pharmacologic effects related to exposure to nusinersen.
A key non-clinical concern based on results from two repeat-dose toxicity studies in juvenile monkeys is a potential for neurotoxicity. Time- and concentration-dependent hippocampal vacuolation and an associated dose-dependent increase in neuronal and glial cell necrosis and cellular debris were observed in these studies. It is uncertain whether the observed hippocampal vacuolation is purely a tissue fixation artifact, as the sponsor has concluded, or whether it represents the onset of neurodegeneration. The presence of vacuolation in a specific area of the hippocampus and not in other cortical areas with higher tissue concentrations of nusinersen, and the dose-dependent increase in neuronal and glial cell necrosis and cellular debris are cause for concern and suggest that the effect may not be due to fixation processes. Furthermore, the observed relatively high tissue concentration and much longer elimination half-life of nusinersen in the hippocampus compared to other brain areas in monkeys (275 days vs. 103-164 days for other brain tissues), indicate nusinersen accumulation in this area, which may exacerbate neurotoxicity. Deficits in learning and habituation to a learning paradigm (both of which are hippocampal-dependent processes) were also observed in high-dose animals in comparison to lower-dose animals in one of these studies, although this effect did not reach statistical significance. The clinical relevance of the hippocampal findings in monkeys is uncertain. Importantly, there is no safety margin for these changes because the concentrations at which they occurred were within the recommended clinical dose range.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Spinraza Product Monograph. In view of the intended use of Spinraza, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Spinraza Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The Chemistry and Manufacturing information submitted for Spinraza has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the product is stored at 5°C±3°C, protected from light, or up to 14 days at or below 30°C.
Proposed limits of related substances impurities, while slightly higher than what would be considered qualified from a non-clinical toxicology perspective, are nonetheless considered acceptable given the indication and dosing of Spinraza.
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
No excipients of human or animal origin are used for the manufacture of the drug product.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| SPINRAZA | 02465663 | BIOGEN CANADA INC | NUSINERSEN (NUSINERSEN SODIUM) 2.4 MG / ML |