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Device/Product name
Welireg
Active Ingredient
Belzutifan
Date of decision
Published
Submission type
New chemical entity
ATC codes
L01XX74
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 Welireg 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

Designation (Orphan)

2 February 2022

Submission dossier accepted and first round evaluation commenced

31 March 2021

First round evaluation completed

14 September 2021

Sponsor provides responses on questions raised in first round evaluation

15 November 2021

Second round evaluation completed

14 January 2022

Delegate’s Overall benefit-risk assessment

14 October 2022

Sponsor’s pre-Advisory Committee response

Not applicable

Advisory Committee meeting

Not applicable

Registration decision (Outcome)

20 December 2022

Completion of administrative activities and registration on ARTG

22 December 2022

Number of working days from submission dossier acceptance to registration decision*

247

*Statutory timeframe for standard applications is 255 working days

Date of entry onto ARTG
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
Tablet
Strength
40 mg
Other ingredients

Croscarmellose sodium, hypromellose acetate succinate, magnesium stearate, mannitol, microcrystalline cellulose, silicon dioxide, indigo carmine aluminium lake, macrogol, polyvinyl alcohol, purified talc and titanium dioxide.

Containers
Bottle
Pack sizes
90 tablets
Routes of administration
Oral
Dosage

The recommended dose is 120 mg administered 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.
What was approved

Welireg (belzutifan) was approved for the following therapeutic use:

WELIREG (belzutifan) is indicated for the treatment of adult patients with von Hippel‑Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) haemangioblastomas, or pancreatic neuroendocrine tumours (pNET), not requiring immediate surgery.

What is this medicine and how does it work
Belzutifan is an inhibitor of hypoxia-inducible factor 2 alpha (HIF-2α). HIF-2α is a transcription factor that plays a role in oxygen sensing by regulating genes that promote adaptation to hypoxia. Under normal oxygen levels, HIF-2α is targeted for ubiquitin-proteasomal degradation by VHL protein. Lack of functional VHL protein results in stabilization and accumulation of HIF-2α. Upon stabilization, HIF-2α translocates into the nucleus and interacts with hypoxia-inducible factor 1 beta (HIF-1β) domains to form a transcriptional complex that induces expression of downstream genes, including genes associated with cellular proliferation, angiogenesis, and tumour growth. Belzutifan binds to HIF-2α, and in conditions of hypoxia or impairment of VHL protein function, belzutifan blocks the HIF-2α-HIF-1β interaction, leading to reduced transcription and expression of HIF-2α target genes. In vivo, belzutifan has demonstrated anti-tumour activity in mouse xenograft models of clear cell renal cell carcinoma (ccRCC).
What post-market commitments will the sponsor undertake
  • Welireg (belzutifan) is to be included in the Black Triangle Scheme. The PI [Product Information] and CMI [Consumer Medicines Information] for Welireg 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 Welireg Core-Risk Management Plan (RMP) (version 3.0, dated 26 October 2021, data lock point 1 June 2020), with Australia specific annex (version 0.6, dated September 2022), included with submission PM-2021-00644-1-4, to be revised to the satisfaction of the TGA, and any subsequent revisions, 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 (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.

  • Submit for evaluation carcinogenicity studies conducted in mouse and rat models.
  • Submit for evaluation any interim analyses and the final analysis of Study MK-6482-004.
  • Submit for evaluation the final study report for study MK-6482-015.

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