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Rholistiq
Sponsor
Device/Product name
Rholistiq
Active Ingredient
Belumosudil mesilate
Date of decision
Published
Submission type
New chemical entity
ATC codes
Not yet assigned
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 Rholistiq 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, 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.
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
Film coated tablet
Strength
200 mg
Other ingredients
Colloidal anhydrous silica, croscarmellose sodium, hypromellose, iron oxide yellow, macrogol 3350, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, purified talc, titanium dioxide
Containers
Bottle
Pack sizes
30
Routes of administration
Oral
Dosage
The recommended dose of Rholistiq is 200 mg given orally once daily.
For further information refer to the Product Information.
Pregnancy category
DDrugs 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
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.
What is this medicine and how does it work
Belumosudil is a potent and selective inhibitor of Rho-associated, coiled coil containing protein kinase-2 (ROCK2). In chronic graft versus host disease (GVHD), naïve thymus cells (T-cells) are skewed to a pro-inflammatory T-cell phenotype, known as T-helper 17 (Th17) cells, with aberrant activation of ROCK2 promoting the synthesis of the pro-inflammatory cytokines interleukin (IL) 17 and IL-21. ROCK2 activation is also recognised to promote pro-fibrotic processes and suppress regulatory T cells. In vitro, belumosudil was shown to suppress IL-17 and IL-21 release from human peripheral blood mononuclear cells and to shift the Th17/regulatory T-cells (Treg) balance of human T cells (mediated via downregulation of signal transducer and activator of transcription (STAT)3 phosphorylation and upregulation of STAT5 phosphorylation, respectively). Anti-fibrotic activity was evident for belumosudil in experiments with cultured human lung fibroblasts. In vivo, belumosudil demonstrated efficacy in mice models of chronic GVHD.
What post-market commitments will the sponsor undertake
- 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.