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Exkivity
ARTGs
370160
Device/Product name
Exkivity
Active Ingredient
Mobocertinib
Date of decision
Published
Submission type
New chemical entity
ATC codes
Not yet assigned
Decision
Approved for provisional registration
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 Exkivity was considered favourable for the therapeutic use approved.
What steps were involved in the decision process
Registration timeline
This evaluation was facilitated through Project Orbis, an initiative of the United States (US) Food and Drug Administration (FDA) Oncology Center of Excellence (OCE). Under this project, the FDA and the TGA collaboratively reviewed the application. This innovative evaluation process provided a framework for process alignment and management of evaluation issues in real-time across jurisdictions.
Each regulator agency maintained its regulatory process to make independent decisions about the approval (market authorisation).
| Description | Date |
|---|---|
| Determination (Provisional) | 27 May 2021 |
| Submission dossier accepted and first round evaluation commenced | 2 August 2021 |
| First round evaluation completed | 24 December 2021 |
| Sponsor provides responses on questions raised in first round evaluation | 23 February 2022 |
| Second round evaluation completed | 20 April 2022 |
| Delegate's overall benefit-risk assessment | 28 June 2022 |
| Sponsor's pre-Advisory Committee response | Not applicable |
| Advisory Committee meeting | Not applicable |
| Registration decision (Outcome) | 14 July 2022 |
| Completion of administrative activities and registration on ARTG | 19 July 2022 |
| Number of working days from submission dossier acceptance to registration decision* | 199 |
*Statutory timeframe for standard applications is 255 working days
Date of entry onto ARTG
Original publication date
Black triangle scheme
Yes. As a provisionally registered product, this medicine will remain in the Black Triangle Scheme for the duration of its provisional registration
Dose forms
Hard capsule
Strength
40 mg
Other ingredients
Exkivity contains no inactive ingredients. The capsule shell contains gelatin, titanium dioxide and TekPrint SW-9008
Containers
Blister pack
Pack sizes
112 capsules
Routes of administration
Oral
Dosage
The recommended dosage of Exkivity is 160 mg orally once daily, continued until disease progression or unacceptable toxicity. It should be taken at approximately the same time each day; and can be taken with or without food.
For further information refer to the Product Information.
Pregnancy category
D
Drugs 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.
Drugs 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
Exkivity (mobocertinib) was approved for the following therapeutic use:
Exkivity has provisional approval in Australia for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that has an exon 20 insertion mutation of the epidermal growth factor receptor (EGFR), who have received prior platinum-based chemotherapy.
The decision to approve this indication has been made on the basis of objective response rate and duration of response in a single arm study. Continued approval of this indication depends on verification and description of benefit in a confirmatory study.
What is this medicine and how does it work
Mobocertinib is a kinase inhibitor of the epidermal growth factor receptor (EGFR) that irreversibly binds to and inhibits EGFR harbouring an exon 20 insertion mutation at lower concentrations than wild type (WT)-EGFR. Two pharmacologically active metabolites (AP32960 and AP32914) with similar inhibitory profiles to mobocertinib have been identified in the plasma after oral administration of mobocertinib. In vitro, mobocertinib also inhibited the activity of EGFR family members (human epidermal growth factor receptor 2 [HER2] and human epidermal growth factor receptor 4 [HER4]), and one additional kinase (B lymphoid tyrosine kinase [BLK]) at clinically relevant concentrations (half maximal inhibitory concentration (IC50) values < 2 nM).
In cell culture models, mobocertinib inhibited the proliferation of cells driven by different EGFR exon 20 insertion mutation variants at 1.5- to 10-fold lower concentrations than those required for WT-EGFR signalling inhibition.
In murine tumour implantation models, mobocertinib demonstrated anti-tumour activity against xenografts carrying either the NPH or the ASV EGFR exon 20 insertion mutation.
In cell culture models, mobocertinib inhibited the proliferation of cells driven by different EGFR exon 20 insertion mutation variants at 1.5- to 10-fold lower concentrations than those required for WT-EGFR signalling inhibition.
In murine tumour implantation models, mobocertinib demonstrated anti-tumour activity against xenografts carrying either the NPH or the ASV EGFR exon 20 insertion mutation.
What post-market commitments will the sponsor undertake
- Exkivity (mobocertinib) is to be included in the Black Triangle Scheme. The Product Information (PI) and Consumer Medicines Information (CMI) for Exkivity must include the black triangle symbol and mandatory accompanying text for 5 years, or for the product's entire period of provisional registration, whichever is longer.
- The Exkivity European Union (EU)-risk management plan (RMP) (version 0.3, dated 11 February 2022, data lock point 23 December 2020), with Australia specific annex (version 2.0, dated 14 February 2022), included with Submission PM-2021-02546-1-4, 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, or the entire period of provisional registration, whichever is longer.
- 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.
- Confirmatory trial data (as identified in the sponsor's plan to submit comprehensive clinical data on the safety and efficacy of the medicine before the end of the 6 years that would start on the day that registration would commence) must be provided.
- Specifically, the sponsor must conduct studies as described in the clinical study plan inversion 2.0 (dated 14 February 2022) of the Australia-specific annex. The following should be submitted to TGA:
- All interim and final clinical study reports for Study TAK-788-3001 (interim and final), with the next analysis expected to be performed in 2023.
- Further guidance for sponsors is available on the TGA website.
- Submit post-market assessments to better characterise the risks of QTc prolongation/Torsades de Pointes and cardiac failure. Expected availability first quarter of 2024.
- Submit the results of Study TAK-788-1007 with regard to the effect of severe renal impairment on mobocertinib pharmacokinetics. Expected availability first quarter of 2023.
- Submit the results of Study TAK-788-1008 with regard to the effect of moderate to severe hepatic impairment on mobocertinib pharmacokinetics. Expected availability fourth quarter of 2022.
- Submit the results of a clinical study with regard to the effects of concurrent administration of mobocertinib on the pharmacokinetics of a BRCP substrates. Expected availability fourth quarter of 2022.