Evrysdi
Sponsor
Device/Product name
Evrysdi
Active Ingredient
Risdiplam
Date of decision
Published
Submission type
New chemical entity
ATC codes
M09AX10
Decision
Approved
What was the decision based on
The decision was based on quality (chemistry and manufacturing), nonclinical (pharmacology and toxicology), clinical (pharmacology, safety and efficacy) and risk management plan information submitted by the sponsor. The benefit-risk profile of Evrysdi was considered favourable for the therapeutic use approved.
What steps were involved in the decision process
Registration timeline
The following table summarises the key steps and dates for this application, evaluated through Priority Review.
| Description | Date |
|---|---|
| Positive Designation (Orphan) | 30 June 2020 |
| Submission dossier accepted and first round evaluation commenced | 31 August 2020 |
| Evaluation completed | 23 February 2021 |
| Delegate's overall benefit-risk assessment and request for Advisory Committee advice | 3 March 2021 |
| Sponsor's pre-Advisory Committee response | 17 March 2021 |
| Advisory Committee meeting | 8 and 9 April 2021 |
| Registration decision (Outcome) | 2 June 2021 |
| Completion of administrative activities and registration on ARTG | 2 June 2021 |
| Number of working days from submission dossier acceptance to registration decision* | 145 |
*Target timeframe for priority applications is 150 working days from acceptance for evaluation to the decision.
Date of entry onto ARTG
Original publication date
Black triangle scheme
Yes. This product will remain in the scheme for 5 years, starting on the date the product is first supplied in Australia
Dose forms
Powder for oral liquid
Strength
0.75 mg/mL
Other ingredients
Mannitol, isomalt, strawberry flavour PHS-180152, tartaric acid, sodium benzoate, macrogol 6000, sucralose, ascorbic acid and disodium edetate
Containers
Bottle
Pack sizes
One
Routes of administration
Oral and nasogastric
Dosage
The recommended once daily dose of Evrysdi for spinal muscular atrophy (SMA) patients is determined by age and body weight.
For further information refer to the Product Information.
Pregnancy category
DDrugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.The use of any medicine during pregnancy requires careful consideration of both risks and benefits by the treating health professional. This must not be used as the sole basis of decision making in the use of medicines during pregnancy. The TGA does not provide advice on the use of medicines in pregnancy for specific cases. More information is available from obstetric drug information services in your State or Territory.
What was approved
Evrysdi (risdiplam) was approved for the following therapeutic use:
Evrysdi is indicated for the treatment of 5q spinal muscular atrophy (SMA) in patients aged 2 months and older.
What is this medicine and how does it work
Evrysdi is a survival of motor neuron (SMN)2 pre-messenger ribonucleic acid (mRNA) splicing modifier designed to treat spinal muscular atrophy (SMA) caused by mutations in chromosome 5q that lead to SMN protein deficiency. Functional SMN protein deficiency is the pathophysiological mechanism of all SMA types. Evrysdi corrects the splicing of SMN2 to shift the balance from exon 7 exclusion to exon 7 inclusion into the mRNA transcript leading to an increased production in functional and stable SMN protein. Thus, Evrysdi treats SMA by increasing and sustaining functional SMN protein levels.In vitro and in vivo data indicate that risdiplam may cause alternative splicing of additional genes, including forkhead box protein M1 (FOXM1) and mitogen activated protein kinase activating death domain (MADD). FOXM1 and MADD are thought to be involved in cell cycle regulation and apoptosis, respectively, and have been identified as possible contributors to adverse effects seen in animals.Risdiplam distributes evenly to all parts of the body, including the central nervous system (CNS) by crossing the blood brain barrier, and thereby leading to SMN protein increase in the CNS and throughout the body. Concentrations of risdiplam in plasma and SMN protein in blood reflect its distribution and pharmacodynamic effects in tissues such as brain and muscle.In all clinical trials, Evrysdi led to a consistent and durable increase in SMN protein with a greater than two fold median change from baseline within four weeks of treatment initiation as measured in blood. This increase in SMN protein was sustained throughout the treatment period of up to two years for infantile onset SMA and later onset SMA patients (see Section 5.1 Clinical trials).
What post-market commitments will the sponsor undertake
- Evrysdi (risdiplam) is to be included in the Black Triangle Scheme. The Product Information (PI) and Consumer Medicines Information (CMI) for Evrysdi must include the black triangle symbol and mandatory accompanying text for five years, which starts from the date that the sponsor notifies the TGA of supply of the product.
- The Evrysdi European Union (EU)-risk management plan (RMP) (version 1.0, dated 5 March 2021, data lock point (DLP) 31 January 2020), with Australian Specific Annex (version 2.1, dated 27 May 2021), included with Submission PM-2020-03580-1-3, and any subsequent revisions, as agreed with the TGA will be implemented in Australia.
An obligatory component of RMPs is routine pharmacovigilance. Routine pharmacovigilance includes the submission of periodic safety update reports (PSURs).
Reports are to be provided in line with the current published list of EU reference dates and frequency of submission of PSURs until the period covered by such reports is not less than three years from the date of the approval letter.
The reports are to at least meet the requirements for PSURs as described in the European Medicines Agency's Guideline on Good Pharmacovigilance Practices (GVP) Module VII-periodic safety update report (Rev 1), Part VII.B Structures and processes. Note that submission of a PSUR does not constitute an application to vary the registration.
- The sponsor to provide the final study reports for each of the following studies:
- Study BP39056
- Study BP39055
- Study BP39054
- Study BP42066
- integrated safety analysis
- thorough QT study