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Empaveli
Sponsor
Device/Product name
Empaveli
Active Ingredient
Pegcetacoplan
Date of decision
Published
Submission type
New chemical entity
ATC codes
L04AA54
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 Empaveli 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.
| Description | Date |
|---|---|
| Designation (Orphan) | 4 September 2020 |
| Submission dossier accepted and first round evaluation commenced | 30 November 2020 |
| First round evaluation completed | 6 May 2021 |
| Sponsor provides responses on questions raised in first round evaluation | 5 July 2021 |
| Second round evaluation completed | 16 August 2021 |
| Delegate's overall benefit-risk assessment | 28 December 2021 |
| Sponsor's pre-Advisory Committee response | Not applicable |
| Advisory Committee meeting | Not applicable |
| Registration decision (Outcome) | 28 January 2022 |
| Completion of administrative activities and registration on ARTG | 3 February 2022 |
| Number of working days from submission dossier acceptance to registration decision* | 243 |
*Statutory timeframe for standard applications is 255 working days
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
Solution for injection
Strength
1080 mg/20 mL
Other ingredients
Sorbitol, glacial acetic acid, sodium acetate trihydrate, sodium hydroxide, and water for injections
Containers
Vial
Pack sizes
1 and 8 vials
Routes of administration
Subcutaneous
Dosage
Before receiving treatment with Empaveli
For patient with known history of vaccination, ensure that patients have received vaccines against encapsulated bacteria including Streptococcus pneumoniae, Neisseria meningitidis types A, C, W, Y, and B, and Haemophilus influenzae type B within 2 years prior to starting Empaveli. For patient without known history of vaccination, administer required vaccines at least 2 weeks prior to receiving the first dose of Empaveli. If immediate therapy with Empaveli is indicated, administer required vaccines as soon as possible and provide patients with antibacterial drug prophylaxis until 2 weeks after vaccination (see Section 4.4 Special warnings and precautions for use of the Product Information).
Adult patients with paroxysmal nocturnal hemoglobinuria
Empaveli is administered twice weekly as a 1,080 mg subcutaneous infusion with a commercially available syringe system infusion pump that can deliver doses up to 20 mL (see method of administration and instructions for use of the Product Information).
Patients switching to Empaveli from a complement component 5 inhibitor (eculizumab rmc, ravulizumab rch)
For the first 4 weeks, Empaveli is administered as twice weekly subcutaneous doses of 1,080 mg in addition to the patient’s current dose of complement component 5 (C5) inhibitor treatment to minimise the risk of haemolysis with abrupt treatment discontinuation. After 4 weeks, the patient should discontinue treatment with the C5 inhibitor before continuing on monotherapy with Empaveli.
Dosage is also based on the lactate dehydrogenase level of the patient.
For further information refer to the Product Information.
Pregnancy category
B3Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed.Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans. 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
Empaveli (pegcetacoplan) was approved for the following therapeutic use:
Empaveli is indicated in the treatment of adult patients with paroxysmal nocturnal haemoglobinuria (PNH) who have an inadequate response to, or are intolerant of, a C5 inhibitor.
What is this medicine and how does it work
Pegcetacoplan binds to complement protein C3 (also known as complement component 3) and its activation fragment C3b with high affinity, thereby regulating the cleavage of C3 and the generation of downstream effectors of complement activation. In paroxysmal nocturnal haemoglobinuria (PNH), extravascular haemolysis (EVH) is facilitated by C3b opsonization while intravascular haemolysis (IVH) is mediated by the downstream membrane attack complex (MAC). Pegcetacoplan exerts broad regulation of the complement cascade by acting proximal to both C3b and MAC formation, thereby controlling the mechanisms that lead to EVH and IVH. These functions of pegcetacoplan underlie the observed sustained reduction in complement-mediated haemolytic activity in patients with PNH.
What post-market commitments will the sponsor undertake
- Empaveli (pegcetacoplan) is to be included in the Black Triangle Scheme. The [Product Information] PI and [Consumer Medicines Information] CMI for Empaveli 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 pegcetacoplan [European Union] EU - risk management plan (RMP) (version 0.2; 23 July 2021, data lock point 31 May 2020), with Australian specific annex (version 0.3, dated 26 August 2021), included with Submission PM-2020-05447-1-6, 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).
Unless agreed separately between the supplier who is the recipient of the approval and the TGA, the first report must be submitted to TGA no later than 15 calendar months after the date of the approval letter. The subsequent reports must be submitted no less frequently than annually from the date of the first submitted report until the period covered by such reports is not less than three years from the date of the approval letter. The annual submission may be made up of two PSURs each covering six months. If the sponsor wishes, the six monthly reports may be submitted separately as they become available.
If the product is approved in the EU during the three years period, reports can be provided in line with the published list of EU reference dates no less frequently than annually from the date of the first submitted report 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 ([revision] 1), part VII.B structures and processes. Note that submission of a PSUR does not constitute an application to vary the registration. Each report must have been prepared within ninety calendar days of the data lock point for that report.
- The sponsor must implement a controlled access program to mitigate the important risk of serious infection as agreed to by the TGA prior to implementation.
- [The sponsor to] provide the following the clinical study reports for the following studies for evaluation:
- The final report for Study APL2-302, a phase III randomised, multicentre, open-label, active-comparator controlled study to evaluate the efficacy and safety of pegcetacoplan in patients with paroxysmal nocturnal haemoglobinuria (PNH).
- The final report for Study APL2-307, an open-label, nonrandomised, multicentre, extension study to evaluate the long-term safety and efficacy of pegcetacoplan for the treatment of PNH in patients who have completed another pegcetacoplan clinical study.
- The final report for Study APL2-308, a phase III randomised, multicentre, open-label, controlled study to evaluate the efficacy and safety of pegcetacoplan as monotherapy compared to standard of care (excluding complement inhibitors) in patients with PNH.
- The sponsor should also further develop studies to evaluate the development of anti-drug antibodies, and neutralising antibodies.
- For all injectable products the Product Information must be included with the product as a package insert.