Zilbrysq (zilucoplan)
The safety and efficacy of zilucoplan were evaluated in:
-a 12-week multicentre, randomised, double-blind placebo-controlled study MG0010 (RAISE) and
-an open-label extension study MG0011 (RAISE-XT) (Open label extension studies usually follow a double blind randomised placebo controlled trial of a new drug after which patients have the option of enrolling in the extension study. In the extension phase, there is no blinding, so both patients and investigators are aware that all patients have been given the drug). Open label extension studies aim to give insight into the safety and tolerability of the drug in the long term.
In the RAISE study, a total of 174 patients were enrolled, who were at least 18 years of age, had anti-AChR antibody positive gMG, MGFA Class II-IV (mild to severe), a Myasthenia Gravis Activities of Daily Living (MGADL) Score of ≥6 and a Quantitative Myasthenia Gravis (QMG Score) of ≥12. The primary endpoint was the change from baseline to Week 12 in MGADL total score. MG-ADL is an 8-item patient reported outcome measure assessing impact of gMG on daily function of signs and symptoms
Two hundred patients were enrolled In the open-label extension RAISE-XT study. These patients had completed either the placebo-controlled Phase 2 (MG0009) or Phase 3 RAISE (MG0010) studies. The RAISE-XT/MG0011 study was primarily a safety and tolerability study which was not randomized or placebo-controlled, therefore efficacy was inferred. Efficacy endpoints were: a change-from-baseline in MGADL, QMG, MGC (Myasthenia Gravis Composite score) and the myasthenia gravis quality of life-15 revised (MG-QoL15r) score at Week 12 of the open-label extension period. The results of this open label study demonstrated sustained efficacy through to Week 60.
This submission was evaluated under the standard prescription medicines registration process.
| Submission dossier accepted and first round evaluation commenced | 31 July 2023 |
| Evaluation completed | 30 April 2024 |
| Delegate’s Overall benefit-risk assessment and request for Advisory Committee advice | 7 May 2024 |
| Sponsor’s pre-Advisory Committee response | 17 May 2024 |
| Advisory Committee meeting | 7 June 2024 |
| Registration decision (Outcome) | 31 July 2024 |
| Administrative activities and registration in the ARTG completed | 20 August 2024 |
| Number of working days from submission dossier acceptance to registration decision* | 255 |
*Statutory timeframe for standard submissions is 255 working days
• pre-filled syringe of 0.574 mL contains zilucoplan tetrasodium, equivalent to 23.0 mg of zilucoplan
• pre-filled syringe of 0.810 mL contains zilucoplan tetrasodium, equivalent to 32.4 mg of zilucoplan
monobasic sodium phosphate monohydrate, dibasic sodium phosphate, sodium chloride and water for injections
Each pre-filled syringe is pre-assembled with a needle safety device, a finger grip and a coloured plunger.
Multipack containing 28 (4 packs of 7) pre-filled syringes.
The recommended dose corresponds to approximately 0.3 mg/kg, given as a once daily subcutaneous injection.
The proposed dosing is weight-based, as follows:
• ≥43 to <56kg: 16.6mg
• ≥56 to <77kg: 23.0mg
• ≥77 to <150kg: 32.4mg
There are no data from the use of Zilbrysq in pregnant women. Zilbrysq is not recommended during pregnancy and in women of childbearing potential not using contraception.
Subcutaneous administration of zilucoplan (0, 1, 2, or 4 mg/kg/day) to pregnant monkeys throughout gestation resulted in an increase in embryofetal death at all doses, in the absence of maternal toxicity. A no effect dose for adverse developmental effects in monkeys was not identified. The lowest dose tested was associated with maternal exposures (AUC) similar to that in humans at the maximum recommended human dose.
Data collected from an ex vivo human placental transfer model suggests a low transfer rate of zilucoplan (0.5–1.0%) in the fetal compartment. The clinical relevance of these data in human pregnancies is unknown.
ZILBRYSQ zilucoplan (as tetrasodium) was approved as an add-on to standard therapy for the treatment of generalised myasthenia gravis in adult patients who are anti-acetylcholine receptor antibody positive.
In generalised myasthenia gravis patients, binding of anti-acetylcholine receptor (AChR) auto-antibodies to AChR results in uncontrolled and inappropriate activation of the classical complement pathway. The immune complex formed by the autoantibody-antigen complex activates the C1 component of the classical complement pathway. This leads to a series of enzymatic cleavage steps, culminating in the cleavage of C5 into C5a and C5b and deposition of the cytolytic membrane attack complex (C5b-9, MAC) on the post-synaptic membrane of the neuromuscular junction and subsequent injury to the neuromuscular endplate, leading to failure of neuromuscular transmission.
Zilucoplan inhibits the effects of C5 through a dual mechanism of action. It specifically binds to complement protein C5, thereby inhibiting its cleavage by the C5 convertase to C5a and C5b, which results in a downregulation of the assembly and cytolytic activity of the MAC. Additionally, by binding to the C5b moiety of C5, zilucoplan sterically hinders binding of C5b to C6, which prevents the subsequent assembly and activity of the MAC, should any C5b be formed.
Zilbrysq (zilucoplan) is to be included in the Black Triangle Scheme. The PI and CMI for Zilbrysq must include the black triangle symbol and mandatory accompanying text for five years, which starts from the date of first supply of the product.
Submission to the TGA of the Post Approval Safety Study (PASS) interim and final reports when they become available.
The Zilbrysq EU-Risk Management Plan (RMP) (version 0.4, date 1 September 2023; DLP 31 March 2022), with Australia-Specific Annex (version 2.0, date 22 February 2024), included with submission PM-2023-02775-1-1, and any subsequent revisions, as agreed with the TGA will be implemented in Australia.
An obligatory component of risk management plans 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 this approval letter. Each report must be submitted within ninety calendar days of the data lock point for that report. 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.
More information
The latest Product Information (PI) and Consumer Medicine Information (CMI) can be found by searching the Australian Register of Therapeutic Goods (ARTG).
Australian Public Assessment Reports (AusPARs) can be found by searching our AusPAR dataset.
The latest news and updates regarding therapeutic goods regulation can be found on our news page.