Rholistiq
Registration timeline
The following table summarises the key steps and dates for this application, evaluated through Priority Review.
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), Swissmedic and Medicines and Healthcare products Regulatory Agency (MHRA) 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 |
|---|---|
| Positive Designation (Orphan) | 4 September 2020 |
| Submission dossier accepted and first round evaluation commenced | 18 November 2020 |
| Evaluation completed | 2 September 2021 |
| Delegate's overall benefit-risk assessment and request for Advisory Committee advice | 2 September 2021 |
| Sponsor's pre-Advisory Committee response | 15 September 2021 |
| Advisory Committee meeting | 30 September and 1 October 2021 |
| Registration decision (Outcome) | 11 November 2021 |
| Completion of administrative activities and registration on ARTG | 12 November 2021 |
| Number of working days from submission dossier acceptance to registration decision* | 160 |
*Target timeframe for priority applications is 150 working days from acceptance for evaluation to the decision.
The recommended dose of Rholistiq is 200 mg given orally once daily.
For further information refer to the Product Information.
Rholistiq (belumosudil mesilate) was approved for the following therapeutic use:
Rholistiq is indicated for the treatment of patients with chronic graft-versus-host disease (chronic GVHD) aged 12 years and older who have an inadequate response to corticosteroids.
- Rholistiq (belumosudil mesilate) is to be included in the Black Triangle Scheme. The Product Information (PI) and Consumer Medicines Information (CMI) for Rholistiq 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 Rholistiq European Union (EU) risk management plan (RMP) version 1.0 (dated 13 November 2020; data lock point (DLP) 19 February 2020) with Australian specific annex (version 1.3, dated 13 September 2021), included with Submission PM-2020-05433-1-6, 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 (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 90 calendar days of the DLP for that report.
- The sponsor to conduct a pharmacokinetics trial to compare the relative bioavailability of belumosudil paediatric formulation to belumosudil tablets and develop an age appropriate paediatric formulation of belumosudil.
- The sponsor to conduct a clinical trial to determine the appropriate dose of belumosudil and to assess the safety, efficacy, and pharmacokinetics of belumosudil in paediatric patients with chronic graft versus host disease. Include at least 20 adolescents 12 to less than 17 years old, 4 children 2 to less than 12 years old, and 2 infants 3 months and older to less than 2 years old. Proposed regulatory action.
- The sponsor to conduct an integrated safety analysis using data obtained from clinical trials to further characterise the safety of long term treatment with belumosudil and determine the rate of infections, hypertension and other adverse events. The integrated safety analysis should include all adverse events, major safety events, dose reductions, dose interruptions, withdrawals, and efficacy when all patients have completed at least three years of treatment with belumosudil or withdrew earlier.
- The sponsor to conduct a clinical pharmacokinetic trial evaluating the effect of repeat doses of belumosudil on the single dose pharmacokinetics of a uridine diphosphate glucuronosyltransferase 1A1 gene (UGT1A1) substrate to assess the potential for excessive drug toxicity.
- The sponsor to conduct a clinical pharmacokinetic trial evaluating the effect of repeat doses of belumosudil on the single dose pharmacokinetics of sensitive substrates P‑glycoprotein (P-gp), breast cancer resistance protein (BCRP) and organic anion transport proteins 1b1 (OATP1B1) to assess the potential for excessive drug toxicity.
- The sponsor to conduct a clinical pharmacokinetic trial to determine a safe and appropriate dose of belumosudil in subjects with mild, moderate, and severe hepatic impairment. The final report should include assessment of subjects with mild, moderate and severe hepatic impairment.
- The sponsor to conduct a thorough QT interval (QT)/corrected QT interval (QTc) trial to evaluate the effect of repeat doses of belumosudil on the QT/QTc interval to address the potential for excessive drug toxicity.
- The sponsor to conduct a rodent carcinogenicity study in mice to evaluate the potential for carcinogenicity.
- The sponsor to conduct a rodent carcinogenicity study in rats to evaluate the potential for carcinogenicity.
- The sponsor to conduct an in vitro mechanism based inhibition study (such as the two step dilution method) estimating the inactivation parameters (the rate of enzyme inactivation (kinact) and the inhibitor constant (KI)) of cytochrome 450 (CYP)1A2, CYP2C19 and CYP2D6 enzymes and measuring nonspecific binding of belumosudil to assess the potential of drug interaction with belumosudil on these enzymes.