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Gavreto
Sponsor
ARTGs
N/A
Device/Product name
Gavreto
Active Ingredient
Pralsetinib
Date of decision
Published
Submission type
New chemical entity
ATC codes
L01EX23
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 Gavreto 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.
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, Health Canada (HC) 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) | 29 November 2021 |
| Submission dossier accepted and first round evaluation commenced | 31 January 2022 |
| First round evaluation completed | 30 June 2022 |
| Sponsor provides responses on questions raised in first round evaluation | 30 August 2022 |
| Second round evaluation completed | 5 October 2022 |
| Delegate’s Overall benefit-risk assessment and request for Advisory Committee advice | 25 October 2022 |
| Sponsor’s pre-Advisory Committee response | 15 November 2022 |
| Advisory Committee meeting | 1 December 2022 |
| Registration decision (Outcome) | 29 March 2023 |
| Completion of administrative activities and registration on ARTG | 29 March 2023 |
| Number of working days from submission dossier acceptance to registration decision* | 242 |
*Statutory timeframe for standard applications is 255 working days
Date of entry onto ARTG
Black triangle scheme
Yes
As a provisionally registered product, this medicine will remain in the Black Triangle Scheme for five years, or the duration of its provisional registration, whichever is longer
As a provisionally registered product, this medicine will remain in the Black Triangle Scheme for five years, or the duration of its provisional registration, whichever is longer
Dose forms
Capsule
Strength
100 mg
Other ingredients
Capsule: Hypromellose, microcrystalline cellulose, sodium bicarbonate, anhydrous citric acid, magnesium stearate, pregelatinized starch
Capsule shell: hypromellose, titanium dioxide, brilliant blue FCF
Printing ink: TekPrint SW-0012 white ink
Containers
Bottle
Pack sizes
60, 90 and 120 capsules
Routes of administration
Oral
Dosage
The recommended dose of Gavreto for adults is 400 mg given orally, once daily.
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
Gavreto (pralsetinib) was provisionally approved for the following therapeutic use:
Non-Small Cell Lung Cancer (NSCLC)
Gavreto has provisional approval in Australia for the treatment of adult patients with locally advanced or metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC). The decision to approve this indication has been made on the basis of overall response rate (ORR) and duration of response (DOR) in single-arm trials. Continued approval of this indication depends on verification and description of benefit in confirmatory trials.
What is this medicine and how does it work
Pralsetinib is a tyrosine kinase inhibitor that targets oncogenic rearranged during transfection (RET) fusions and mutations, including V804 gatekeeper mutations associated with resistance to other therapies. In vitro, pralsetinib inhibited several oncogenic RET fusions and mutations (CCDC6 RET, RET V804L, RET V804M and RET M918T) with half maximal inhibitory concentrations at clinically relevant concentrations. In a broad panel of purified enzyme assays, pralsetinib demonstrated the highest selectivity for RET.
RET fusion proteins and activating point mutations can drive tumorigenic potential through hyperactivation of downstream signalling pathways leading to uncontrolled cell proliferation. Pralsetinib exhibited anti-tumour activity in cultured cells and animal tumour implantation models representing multiple tumour types harbouring oncogenic RET fusions or mutations (KIF5B-RET, CCDC6-RET, RET M918T, RET C634W, as well as the V804L and V804M mutants associated with cabozantinib and vandetanib resistance).
RET fusion proteins and activating point mutations can drive tumorigenic potential through hyperactivation of downstream signalling pathways leading to uncontrolled cell proliferation. Pralsetinib exhibited anti-tumour activity in cultured cells and animal tumour implantation models representing multiple tumour types harbouring oncogenic RET fusions or mutations (KIF5B-RET, CCDC6-RET, RET M918T, RET C634W, as well as the V804L and V804M mutants associated with cabozantinib and vandetanib resistance).
What post-market commitments will the sponsor undertake
- Gavreto (pralsetinib) is to be included in the Black Triangle Scheme. The PI [Product Information] and CMI [Consumer Medicine Information] for Gavreto must include the black triangle symbol and mandatory accompanying text for five years, or the product’s entire period of provisional registration, whichever is longer.
- The Gavreto EU [European Union]-Risk Management Plan (RMP) (version 1.2, dated 3 February 2022 data lock point January 2022), with Australian Specific Annex (version 1.1, dated 26 August 2022), included with submission PM-2021-05760-1-4; PM-2021-05761-1-4 and PM-2021-05762-1-4, 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 (Rev 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.
- Longer follow up of efficacy evaluable patients (116 treatment naïve patients and more follow up of the 136 NSCLC previously treated with platinum therapy) from the relevant cohorts from study ARROW (BLU-667-1101).
- Confirmatory data from the ongoing AcceleRET Lung study (BLU-667-2303), an open-label, randomized, controlled multi-centre phase III study in RET fusion-positive NSCLC patients; this study is designed to assess the efficacy of pralsetinib as compared to Investigator’s choice platinum-based chemotherapy regimen (with or without pembrolizumab) for patients with metastatic NSCLC harbouring an oncogenic RET fusion and who have not received prior systemic therapy. Submission of the final report is expected by Q4 2026.
- Comprehensive analysis evaluating and characterising the incidence, clinical presentation, management and outcome of the potential serious risk of pralsetinib associated gastrointestinal perforations and fistulas. Submit an integrated final report containing data from patient-level and pooled analyses of ongoing and completed clinical trials, post-marketing reports and/or literature reports and a comprehensive pharmacovigilance assessment for this risk.
- Conduct a hepatic impairment clinical trial to evaluate the pharmacokinetics and safety of pralsetinib in subjects with moderate and severe hepatic impairment compared to subjects with normal hepatic function. Design and conduct the trial in accordance with FDA guidance and submit the datasets with the final report.
- Conduct a clinical drug-drug interaction study to evaluate the effect of repeat doses of a P-gp inhibitor on the pharmacokinetics of pralsetinib and to inform appropriate dosing strategies for safe co-administration of pralsetinib with P-gp inhibitors. Design and conduct the trial in accordance with FDA guidance and submit the datasets with the final report.
- Conduct a physiologically-based pharmacokinetic modelling/simulation study to evaluate the effect of repeat doses of a moderate CYP3A inhibitor on the pharmacokinetics of pralsetinib, assess the magnitude of increased pralsetinib exposure, and inform appropriate dosing strategies for safe co-administration of pralsetinib with moderate CYP3A inhibitors. Design and conduct the trial in accordance with FDA guidance, and submit the model with the final report.
- Conduct a physiologically-based pharmacokinetic modelling/simulation study to evaluate the effect of repeat doses of a combined P-gp and moderate CYP3A inhibitor on the pharmacokinetics of pralsetinib, assess the magnitude of increased pralsetinib exposure, and inform appropriate dosing strategies for safe co-administration of pralsetinib with combined P-gp and moderate CYP3A inhibitors. Design and conduct the trial in accordance with FDA guidance, and submit the model with the final report.
- Conduct a clinical drug interaction study to evaluate the effect of repeat doses of pralsetinib on the pharmacokinetics of transporter substrates of P-gp, BCRP, OATP1B1, OATP1B3, MATE-1 and MATE-2K, assess the magnitude of exposure change, and inform appropriate dosing strategies for co-administration of pralsetinib with these transporter substrates. Design and conduct the trial in accordance with FDA guidance, and submit the datasets with the final report.
- Conduct a clinical drug interaction study to evaluate the effect of repeat doses of pralsetinib on the pharmacokinetics of sensitive substrates of CYP3A4/5, CYP2C8, and CYP2C9, assess the magnitude of exposure change, and inform appropriate dosing strategies for safe co-administration of pralsetinib with sensitive substrates of CYP3A4/5, CYP2C8 and CYP2C9. Design and conduct the trial in accordance with FDA guidance, and submit the datasets with the final report.
- Conduct a physiologically-based pharmacokinetic modelling/simulation study to evaluate the effect of repeat doses of a moderate CYP3A inducer on the pharmacokinetics of pralsetinib, assess the magnitude of decreased pralsetinib exposure, and inform appropriate dosing strategies for co-administration of pralsetinib with moderate CYP3A inducers. Design and conduct the trial in accordance with FDA guidance, and submit the model with the final report.