Summary Basis of Decision for Evrysdi
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 Evrysdi is located below.
Recent Activity for Evrysdi
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.
Summary Basis of Decision (SBD) for Evrysdi
Date SBD issued: 2021-07-27
The following information relates to the new drug submission for Evrysdi.
Risdiplam
Drug Identification Number (DIN):
- DIN 02514931 - 0.75 mg/mL risdiplam, powder for solution, oral administration
Hoffmann-La Roche Ltd.
New Drug Submission Control Number: 242373
On April 14, 2021, Health Canada issued a Notice of Compliance to Hoffmann-La Roche Limited for the drug product Evrysdi.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit-harm-uncertainty profile of Evrysdi is favourable for the treatment of spinal muscular atrophy in patients 2 months and older.
There are limited data on Evrysdi for patients over 25 years of age.
1 What was approved?
Evrysdi, a splicing modifier, was authorized for the treatment of spinal muscular atrophy (SMA) in patients 2 months and older.
There are limited data on Evrysdi for patients over 25 years of age.
Health Canada has authorized an indication for pediatric use in patients 2 months and older. The safety and efficacy of Evrysdi has been established in this population based on the data reviewed in connection with this submission. In the limited number of patients aged 2 to 5 months who received the recommended dose in clinical trials, higher drug exposures are predicted compared to older infants, which further narrow the safety margins in this age group. Evrysdi is not indicated in infants younger than 2 months of age, as no data are available in this patient population.
Evrysdi has not been studied in patients with SMA above 60 years of age.
Evrysdi is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
Evrysdi 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.
Evrysdi (0.75 mg/mL risdiplam) is presented as a powder for solution. In addition to the medicinal ingredient, the powder contains ascorbic acid, disodium edetate dihydrate, isomalt, macrogol/polyethylene glycol 6000, mannitol, sodium benzoate, strawberry flavor, sucralose, and tartaric acid.
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 Evrysdi Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Evrysdi approved?
Health Canada considers that the benefit-harm-uncertainty profile of Evrysdi is favourable for the treatment of spinal muscular atrophy (SMA) in patients 2 months and older.
There are limited data on Evrysdi for patients over 25 years of age.
Spinal muscular atrophy is an autosomal recessive neuromuscular disorder. It is the most common genetic cause of infant mortality, with an estimated incidence of 1 in 6,000 to 1 in 10,000 live births. Approximately 1 in 40 people are genetic carriers. Spinal muscular atrophy is characterized by the degeneration of alpha motor neurons in the spinal cord. The most common cause of SMA is homozygous deletion or mutation of the survival of motor neuron (SMN) 1 gene, which leads to a deficiency of the SMN protein. Clinically, this results in progressive muscle weakness and atrophy, and absent or markedly decreased deep tendon reflexes. Additionally, SMA is associated with restrictive and progressive respiratory insufficiency, particularly in cases of prenatal or infantile onset SMA.
Phenotypes of SMA are classified as types 0 to 4, depending on the age of onset and clinical course of the disease. The most common and severe types of SMA are type 0 (prenatal onset) and type 1 (infantile onset), with type 1 SMA accounting for approximately 60% of cases. In all types of SMA, progressive weakness and impaired motor development are initially observed. This is followed by a slower plateau of relative stability and a long-term decline in strength and movement ability. The impaired motor milestone depends on the type of SMA: unable to lift the head, sit, stand, or walk.
Humans have two nearly identical SMN genes that encode the SMN protein: SMN1 and SMN2. The SMN protein is produced primarily by the SMN1 gene. The SMN2 gene is responsible for only 10% of the full-length protein produced that is functional and stable. In SMA, the number of copies of SMN2 generally correlates inversely with the severity of the disease. However, different patients with the same SMN2 copy number can have different clinical phenotypes.
Treatment for SMA is classified as either supportive or disease-modifying. Supportive therapies include nutrition and respiratory assistance, and the treatment of comorbidities and complications of SMA. At the time of authorization of Evrysdi, two disease-modifying drugs, nusinersen and onasemnogene abeparvovec, were marketed in Canada for the treatment of SMA in pediatric and adult patients.
Risdiplam, the medicinal ingredient in Evrysdi, is a pre-messenger ribonucleic acid (mRNA) splicing modifier of SMN2. A deficiency in functional SMN protein is the pathophysiological mechanism of all SMA types. Risdiplam shifts the balance from exon 7 exclusion to exon 7 inclusion into the mRNA transcript of SMN2, leading to increased production of functional and stable SMN protein. Thus, risdiplam treats SMA by increasing functional SMN protein levels.
The clinical efficacy and safety of Evrysdi were evaluated primarily in two pivotal studies. The FIREFISH study was conducted in patients with infantile-onset SMA (type 1), and the SUNFISH study was conducted in patients with later-onset SMA (types 2 and 3). Both studies had two parts, and patients from Part 1 did not participate in Part 2.
FIREFISH was a two-part, open-label, single-arm study in infants with type 1 SMA, aged 1-7 months at the time of enrollment. Part 1 was a dose-escalation study (in 21 patients) designed to select the therapeutic dose to be used in Part 2. In Part 2, the efficacy, safety, and tolerability of Evrysdi were evaluated in infants with type 1 SMA (in 41 patients).
The primary efficacy endpoint was the proportion of infants who were able to sit without support for at least 5 seconds after 12 months of treatment, and was achieved by 29% of patients in Part 2 of the study. This outcome is clinically and statistically significant, as it exceeded the pre-defined performance criterion of 5% based on natural history data.
In the FIREFISH study, the most frequently reported adverse reactions in patients treated with Evrysdi (2% of patients or greater) were upper respiratory tract infection (74.2%, including nasopharyngitis, rhinitis, respiratory tract infection [bacteria and viral]), pyrexia (48.4%), rash (27.4%), constipation (19.4%), diarrhea (16.1%), vomiting (14.5%), and urinary tract infection (6.5%). Deaths occurred in 9.7% of patients with infantile onset SMA on treatment with Evrysdi and were due to progression of underlying SMA.
SUNFISH was a two-part, double-blind, randomized, placebo-controlled study in patients aged 2-25 years with type 2 or type 3 SMA. Part 1 was the dose-finding portion of the study, designed to select the therapeutic dose to be used in Part 2. In Part 2, patients with a body weight of 20 kg or greater received a 5 mg dose once daily, and patients with a body weight less than 20 kg received a 0.25 mg/kg dose once daily. The treatment period for Part 2 was 24 months long, and patients receiving the placebo were switched to active treatment in a blinded manner after 12 months.
The primary endpoint in Part 2 was the least square mean change from baseline in the 32-item Motor Function Measure (MFM32) between Evrysdi and placebo after 12 months of treatment. The total score is expressed as a percentage of the maximum possible score, with higher scores indicating greater motor function.
The least square mean change was 1.36 points in the Evrysdi group and -0.19 points in the placebo group. The difference of 1.55 points between the two groups is statistically significant. Results of subgroup analyses indicated that the improvement in the MFM32 was the greatest in the younger age group (2-6 years), and decreased with each subgroup of older patients. In the oldest patients (aged 18-25 years), no improvement was observed in the MFM32 relative to baseline measurements.
In the SUNFISH study, the most frequently reported adverse reactions in patients treated with Evrysdi were pyrexia (21.7%), diarrhea (16.7%), rash (16.7%), mouth/aphthous ulcer (6.7%), urinary tract infection (6.7%), and arthralgia (5%). No deaths occurred during this study.
Supplementary safety data was obtained through a supportive safety study, JEWELFISH. The JEWELFISH study was conducted in 174 patients, including 90 who were previously treated with an authorized product: 76 patients previously treated with nusinersen and 14 patients previously treated with onasemnogene abeparvovec. The safety profile of Evrysdi in treating this subset of non-naïve patients in the JEWELFISH study is consistent with the safety profile of Evrysdi in treating naïve SMA patients in the FIREFISH and SUNFISH studies.
A Risk Management Plan (RMP) for Evrysdi was submitted by Hoffmann-La Roche Limited 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.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Evrysdi Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name Evrysdi was accepted.
Evrysdi has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Evrysdi 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 Evrysdi?
The drug submission for Evrysdi was subject to an expedited review process under the Priority Review Policy. The sponsor presented substantial evidence of clinical effectiveness to demonstrate that Evrysdi provides an effective treatment for spinal muscular atrophy (SMA), a life-threatening and severely debilitating condition. Additionally, the oral route of administration of Evrysdi provides a significant decrease in risk relative to existing therapies for a condition not adequately managed by a drug in Canada. At the time of review of the Priority Review request, nusinersen was the only therapy marketed in Canada for the treatment of SMA. Nusinersen is administered intrathecally, which is an invasive route, contraindicated in some patients, and carries potential risks. An orally administered drug has the benefit of avoiding the risks associated with intrathecal administration, resulting in an improved overall benefit/risk profile relative to existing therapies.
Submission Milestones: Evrysdi
| Submission Milestone | Date |
|---|---|
| Request for priority status | |
| Filed | 2020-06-16 |
| Approval issued by Director, Bureau of Medical Sciences | 2020-07-16 |
| Submission filed | 2020-07-30 |
| Screening | |
| Screening Deficiency Notice issued | 2020-08-28 |
| Response filed | 2020-09-17 |
| Screening Acceptance Letter issued | 2020-10-16 |
| Review | |
| Review of Risk Management Plan complete | 2021-03-26 |
| Quality Evaluation complete | 2021-04-09 |
| Biostatistics Evaluation complete | 2021-04-12 |
| Non-Clinical Evaluation complete | 2021-04-12 |
| Labelling Review complete | 2021-04-12 |
| Clinical/Medical Evaluation complete | 2021-04-14 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate | 2021-04-14 |
The Canadian regulatory decision on the review of Evrysdi was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
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
Risdiplam is a pre-messenger ribonucleic acid (mRNA) splicing modifier of survival of motor neuron 2 (SMN2) designed to treat spinal muscular atrophy (SMA), which is caused by mutations in chromosome 5q that lead to SMN protein deficiency. Functional SMN protein deficiency is the pathophysiological mechanism of all SMA types. Risdiplam shifts the balance from exon 7 exclusion to exon 7 inclusion into the SMN2 mRNA transcript, leading to increased production in functional and stable SMN protein. Thus, risdiplam treats SMA by increasing and sustaining functional SMN protein levels.
The clinical pharmacology data submitted in support of Evrysdi included five clinical pharmacology studies in healthy subjects, data from the initial dose-escalation part of both pivotal studies (described in the Clinical Efficacy section), and results from a population pharmacokinetic-pharmacodynamic (PK-PD) modelling analysis.
No significant concerns were identified through the review of the pharmacokinetic data. Steady state was reached in 7-14 days, and the terminal half-life was approximately 50 hours. Risdiplam, the medicinal ingredient in Evrysdi, is metabolized primarily in the liver by flavin-containing monooxygenase (FMO) 1 and 3, and cytochrome P450 (CYP) 3A4. Renal elimination is minimal (approximately 8% unchanged parent drug in urine). Risks associated with drug-drug interactions were determined to be generally minimal.
The results of the final population PK-PD model identified bodyweight and age as significant time-varying covariates on which to adjust dosing. Although the model was satisfactory overall, the data reviewed from the modelling analysis indicated underexposure to risdiplam in patients weighing over 40 kg, and overexposure to risdiplam in patients less than 5 months old.
In patients weighing over 40 kg, the recommended dose of 5 mg once daily resulted in individual exposures below observed exposure range in FIREFISH and SUNFISH (1,060 - 3,800 ng.h/mL). Simulations with a higher dose of 5.5 mg predicted a more optimal exposure range in this subset of patients. However, this dose has not been evaluated in clinical studies (the maximum dose was 5 mg once daily), and exposure is considered as only one of several factors potentially impacting risdiplam efficacy in older/heavier patients. Therefore, the recommended dose is 5 mg, and it is stated that a daily dose above 5 mg has not been studied.
In the FIREFISH study (Parts 1 and 2), only 6 out of 25 patients who started the drug at less than 5 months of age received the recommended 0.2 mg/kg dose (for at least 7 days) while under 5 months. The remainder received 0.08 mg/kg daily while under 5 months. In light of the small number of patients receiving the recommended dose in the clinical trials, and given that simulation of the recommended dose predicted that the subset of patients under 6 months old has higher exposure than older infants, the population pharmacokinetic model was used to simulate a range of doses in 2- to 5-month-old infants, from 0.08 mg/kg to 0.2 mg/kg. These simulations confirmed that the 0.08 mg/kg dose results in exposures below the floor of the observed exposure range (768 ng.h/mL and 1,060 ng.h/mL, respectively). Additionally, they showed that the recommended dose of 0.2 mg/kg results in higher exposures than the observed exposure range in FIREFISH and SUNFISH (4,800 ng.h/mL and 3,800 ng.h/mL, respectively). Given the safety concerns identified in the non-clinical data (retinal toxicity, delayed growth, reproductive system, effects on epithelial cells and bone marrow cellularity, of which some are irreversible or only partially reversible) and the further narrowing of already narrow safety margins with the 0.2 mg/kg dose, there is potential for overexposure of this vulnerable patient population at the recommended dose. Thus, awareness by prescribers of this uncertainty regarding the recommended dosing is considered essential. Findings from the simulations and the limitations of the data are included in the Evrysdi Product Monograph.
A study was conducted in adult subjects to assess the pharmacokinetics of Evrysdi in subjects with hepatic impairment. After administration of a single oral 5 mg dose, the exposure as measured by the area under the concentration-time curve (AUC) and the maximum plasma concentration (Cmax) were compared to the corresponding data in 10 healthy control subjects. The mean ratios for AUC and Cmax were 0.80 and 0.95 in subjects with mild hepatic impairment (Child-Pugh Class A, 8 subjects), and 1.08 and 1.20 in subjects with moderate hepatic impairment (Child-Pugh Class B, 8 subjects). The pharmacokinetics of Evrysdi have not been studied in subjects with severe hepatic impairment. However, the liver appears to be a primary site for the metabolism of Evrysdi, and severe hepatic impairment may result in increased exposure.
No studies have been conducted to assess the pharmacokinetics of Evrysdi in subjects with renal impairment. The elimination of Evrysdi as an unchanged entity via renal excretion is minor (8%). Renal impairment is not expected to alter the exposure to Evrysdi.
For further details, please refer to the Evrysdi Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Evrysdi was evaluated in two pivotal studies. The FIREFISH study was conducted in patients with infantile-onset SMA (type 1), and the SUNFISH study was conducted in patients with later-onset SMA (types 2 and 3). Both studies were conducted in two parts, and patients from Part 1 did not participate in Part 2.
FIREFISH was a two-part, open-label, single-arm study in infants with type 1 SMA (genetically confirmed, with two copies of the SMN2 gene). Patients were aged 1-7 months at the time of enrollment. Part 1 was a dose-escalation study (in 21 patients) designed to select the therapeutic dose to be used in Part 2, during which the efficacy, safety, and tolerability of Evrysdi were evaluated in infants with type 1 SMA (in 41 patients). Patients in Part 1 received a minimum of 4 weeks of treatment for dose selection (at 0.0106, 0.04, 0.08, 0.2, or 0.25 mg/kg once daily), and then continued to receive Evrysdi at a dose of 0.2 mg/kg until Month 24. Starting doses in Part 2 depended on the age of the patients, and were subsequently adjusted to 0.2 mg/kg for all infants younger than 2 years of age. Infants 2 years of age and older received 0.25 mg/kg. Following 24 months of treatment in either part of the study, patients were allowed to enter an open-label extension study.
The primary efficacy endpoint was the proportion of infants who were able to sit without support for at least 5 seconds after 12 months of treatment, as measured by Item 22 of the Bayley Scales of Infant and Toddler Development-Third Edition (BSID-III). This endpoint was achieved by 29% of patients in Part 2 of the study. This outcome is clinically and statistically significant, as it exceeded the pre-defined performance criterion of 5% based on natural history data. Compared to the normal course of the disease, improvements were also observed with respect to the key secondary endpoints of this study following 12 months of treatment with Evrysdi.
SUNFISH was a two-part, double-blind, randomized, placebo-controlled study in patients aged 2-25 years with type 2 or type 3 SMA. Part 1 was the dose-finding portion of the study, designed to select the therapeutic dose to be used in Part 2. In Part 1, patients received a minimum of 12 weeks of placebo-controlled treatment (0.02, 0.05, 0.15, or 0.25 mg/kg in patients aged 2-11 years; 3 mg or 5 mg in patients aged 12-25 years), after which patients receiving the placebo were switched over to receive Evrysdi at the dose tested in their cohort. After the doses for Part 2 were selected, all patients switched to the selected dose according to body weight. In Part 2, patients with a body weight of 20 kg or greater received a 5 mg dose once daily, and patients with a body weight less than 20 kg received a 0.25 mg/kg dose once daily. The treatment period for Part 2 was 24 months long, and patients receiving the placebo were switched to active treatment in a blinded manner after 12 months.
The primary endpoint in Part 1 was the least square mean change from baseline in the 32-item Motor Function Measure (MFM32) between Evrysdi and placebo after 12 months of treatment. The MFM32 can be used to evaluate a wide range of motor functions across a broad range of patients with SMA, and to follow the progression of SMA. The total score is expressed as a percentage of the maximum possible score, with higher scores indicating greater motor function.
The least square mean change was 1.36 points in the Evrysdi group and -0.19 points in the placebo group. The difference of 1.55 points between the two groups was determined to be statistically significant. Results of subgroup analyses indicated that the improvement in the MFM32 was the greatest in the younger age group (2-6 years), and decreased with each subgroup of older patients. In the oldest patients (aged 18-25 years), no improvement was observed in the MFM32 relative to baseline measurements.
The secondary endpoints of the study included the proportion of patients who achieved a change of 3 points or greater on the total MFM32 score, the Revised Upper Limb Module (RULM) score, the Hammersmith Functional Motor Scale (HFMSE) score, the percent Forced Vital Capacity (FVC), the SMA Independence Scale (SMAIS), and the Clinical Global Impression of Change (CGI-C) scale. In the oldest patients, the likelihood of the proportion achieving an improvement of MFM32 by 3 points or greater was slightly higher in the placebo group compared to the Evrysdi group. Due to the progressive nature and natural history of the disease, it is more challenging to achieve a marked improvement for patients with more progressive disease and after certain baseline limitations. The baseline scores for the MFM32, RULM, and HFMSE were lower in the Evrysdi group than in the placebo group in the older patients, which may have influenced the results for this age group. However, an improvement in the RULM score was observed in the 18-25 year age group. Additionally, four patients enrolled in Part 1 of SUNFISH were in the 18-25 year age group, and their long-term data (2 years) indicated a sustained benefit of treatment with Evrysdi.
With respect to the key secondary endpoints, the MFM32 responder analysis (the change from baseline of 3 points or greater) and the change from baseline in the RULM total score at Month 12 were statistically significant. However, the change from baseline in the HFMSE total score at Month 12 and the change from baseline in the FVC best percentage predicted value at Month 12 in patients aged 6-25 years did not achieve statistical significance. The other endpoints were not formally tested due to the hierarchical testing scheme. The change from baseline in the caregiver-reported SMAIS total score at Month 12 was nominally higher in the Evrysdi group than in the placebo group.
Indication| Sponsor's proposed indication | Health Canada-approved indication |
| Evrysdi is indicated for the treatment of spinal muscular atrophy (SMA). |
Evrysdi (risdiplam) is indicated for the treatment of spinal muscular atrophy (SMA) in patients 2 months and older. Adult: There are limited data on Evrysdi for patients over 25 years of age. |
For more information, refer to the Evrysdi Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
Evidence of the clinical safety of Evrysdi was provided primarily through safety data collected in the two pivotal studies, FIREFISH and SUNFISH (described in the Clinical Efficacy section). Supplementary data was obtained through a supportive safety study, JEWELFISH.
In the FIREFISH study, the most frequently reported adverse reactions in patients treated with Evrysdi (2% of patients or greater) were upper respiratory tract infection (74.2%, including nasopharyngitis, rhinitis, respiratory tract infection [bacteria and viral]), pyrexia (48.4%), rash (27.4%), constipation (19.4%), diarrhea (16.1%), vomiting (14.5%), and urinary tract infection (6.5%). Deaths occurred in 9.7% of patients with infantile onset SMA on treatment with Evrysdi and were due to the progression of underlying SMA.
In the SUNFISH study, the most frequently reported adverse reactions in patients treated with Evrysdi were pyrexia (21.7%), diarrhea (16.7%), rash (16.7%), mouth/aphthous ulcer (6.7%), urinary tract infection (6.7%), and arthralgia (5%). No deaths occurred during this study.
The JEWELFISH study was conducted in 174 patients, including 90 who were previously treated with an authorized product: 76 patients previously treated with nusinersen and 14 patients previously treated with onasemnogene abeparvovec. The safety profile of Evrysdi in treating this subset of non-naïve patients in the JEWELFISH study is consistent with the safety profile of Evrysdi in treating naïve SMA patients in the FIREFISH and SUNFISH studies
For more information, refer to the Evrysdi 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 most commonly caused by the homozygous deletion or mutation of the survival of motor neuron (SMN) 1 gene, which results in deficiency of the SMN protein. In in vitro experimental models of SMA, risdiplam (the medicinal ingredient in Evrysdi) increased the levels of full-length SMN messenger RNA (mRNA) and SMN protein. In two transgenic mouse models of SMA, risdiplam was found to increase the levels of SMN protein in brain and muscles. Additionally, risdiplam improved clinical outcomes in mice with severe type SMA.
Non-clinical pharmacokinetic studies were also conducted in rats, mice, rabbits, and monkeys, which compared the absorption of risdiplam following oral and intravenous administration. When administered orally, risdiplam is distributed broadly in the body, including to the central nervous system. The metabolism of risdiplam in human microsomes was mediated primarily by flavin-containing monooxygenase (FMO) 1 and FMO3, with some contribution from cytochrome P450 (CYP) 3A4 and other CYP enzymes.
No serious safety signals were detected during the review of the non-clinical pharmacology and pharmacokinetic studies conducted with risdiplam. However, certain potential risks were identified. Data from in vitro and in vivo studies indicate that risdiplam may cause alternative splicing of additional genes including those encoding the Forkhead box M1 (FOXM1) and MAP kinase-activating death domain (MADD) proteins. The FOXM1 and MADD proteins are thought to be involved in cell cycle regulation and apoptosis, respectively, and these off-target actions are believed to be possible contributors to the adverse effects observed in animals. The clinical relevance of these interactions is unknown.
Although no safety signals were identified in safety pharmacology studies, the dose range tested included but did not exceed the dose used in primary pharmacology studies. The risk of QT prolongation was studied in vitro, and a comprehensive clinical QT/QTc study is ongoing. Risdiplam crosses the placental barrier and is excreted into milk. Studies in pregnant and lactating rats showed that the milk to plasma ratio of drug-related radioactivity was greater than 3 for at least 24 hours after the administration of risdiplam. Additionally, risdiplam is a substrate of breast cancer resistance protein (BCRP) and may be a substrate of multidrug resistant (MDR) 1. It also significantly inhibited multidrug and toxin extrusion (MATE) 1 and MATE2-K in vitro. The clinical relevance of interactions between risdiplam and these transporters is unknown.
Certain key concerns were also identified relating to the narrow safety margin of risdiplam. Signs of retinal toxicity were observed in toxicology studies in monkeys. Microcystic macular degeneration, hyper-reflective retinal epithelium, and peripheral photoreceptor cell loss were observed in a dose- and time-dependent manner in monkeys at doses of 1 mg/kg or greater. Although some of the observed changes were partially reversible after a 22-week recovery phase, other changes, such as the damage to photoreceptors, were not reversible. A study conducted with male rats could not confirm retinopathy, but increased retinal haziness over time was observed. The clinical significance of these observations is unknown. However, the data available are insufficient to draw conclusions regarding long-term or delayed onset retinal toxicity. Signs of delayed growth and reproductive and developmental toxicity were also observed in juvenile rats that received doses of 1 mg/kg risdiplam or greater. Negative effects were observed on growth, and delayed sexual maturation was observed in both male and female rats. Impaired reproductive performance was observed in female rats that received 2.5 mg/kg doses of risdiplam. Epithelial and bone marrow cells were also affected by the administration of risdiplam. Degeneration/necrosis of epithelial cells in the gastrointestinal tract and decreased bone marrow cellularity were identified as a cause of mortality in rats that received doses of 1 mg/kg or greater.
Risdiplam was not found to be mutagenic in bacterial mutagenicity assays, but the results of in vitro and in vivo micronucleus assays indicate that risdiplam has clastogenic potential. There was no evidence of carcinogenicity in a 26-week carcinogenicity study in mice. A two-year rat carcinogenicity study is ongoing, the results of which are expected to provide a more thorough understanding of the carcinogenic potential of risdiplam.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Evrysdi Product Monograph. Considering the intended use of Evrysdi, there are no pharmacological or toxicological issues within this submission that preclude authorization of the product.
For more information, refer to the Evrysdi 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 Evrysdi 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 made to formulation and the manufacturing process throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the product should be stored at room temperature (15 ºC to 25 ºC) in its original bottle prior to reconstitution. After reconstitution, the oral solution should be stored at 2 ºC to 8 ºC for up to 64 days. The solution should not be frozen. Additional storage and special handling instructions are included in the Evrysdi Product Monograph.
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.
The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| EVRYSDI | 02514931 | HOFFMANN-LA ROCHE LIMITED | RISDIPLAM 0.75 MG / ML |