Regulatory Decision Summary for Actemra
The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.
Type of submission:
What was the purpose of this submission?
The purpose of this submission was to seek market authorization in Canada for Actemra (tocilizumab) for the treatment of chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome (CRS). After evaluation of the submitted data package, Health Canada authorized Actemra for the following indication:
Actemra is indicated for the treatment of patients with chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome (CRS), in accordance with patient populations specified for authorized CAR T cell products.
Why was the decision issued?
Cytokine release syndrome (CRS) is a potentially life-threatening adverse reaction of chimeric antigen receptor (CAR) T cell therapy, involving the excessive release of cytokines including interleukin (IL)-6. Actemra (tocilizumab) is a recombinant humanized IgG1κ monoclonal antibody directed against the IL-6 receptor, and can inhibit IL-6 signaling. Tocilizumab is used in clinical trials to manage symptoms of severe or life-threatening CRS resulting from treatment with CAR T cell products, and is included in the CRS management algorithms within the product monographs of authorized CAR T cell therapies.
Due to the nature of CAR T cell-induced CRS, no prospective studies designed to specifically assess the use of tocilizumab in patients with CRS were performed. Thus, a retrospective analysis of clinical trial data from CAR T cell therapies (tisagenlecleucel and axicabtagene ciloleucel) for haematological malignancies and a review of published data provide evidence for the efficacy of tocilizumab in resolving CAR T cell-induced severe or life-threatening CRS. In a retrospective analysis of data from clinical trials for tisagenlecleucel, 69% of patients treated with tocilizumab 8 mg/kg (12 mg/kg for those weighing < 30 kg) achieved response defined as resolution of CRS with administration of ≤ 2 doses of tocilizumab and within 14 days of the first dose of tocilizumab, with no drugs other than tocilizumab and corticosteroids used for treatment. In clinical trials for axicabtagene ciloleucel, 53% of patients achieved response.
In a retrospective analysis of clinical trial data for tisagenlecleucel, no adverse reactions were attributed to treatment with tocilizumab and no new safety concerns related to tocilizumab were identified. The most relevant potential safety concerns with tocilizumab treatment are neutropenia and the potential for infections. These are established safety concerns previously identified for tocilizumab. Tocilizumab has a well-established and manageable safety profile at the recommended weight-based dose (8 mg/kg in patients ≥ 30 kg or 12 mg/kg in patients < 30 kg) in both adults and pediatric patients, based on authorized indications for Actemra. Recommended dosing intervals for tocilizumab may differ between CAR T cell products; thus, for optimal use of tocilizumab, the CRS management algorithm in the appropriate CAR T cell therapy product monograph should be consulted.
Overall, considering the potential for life-threatening complications to accompany severe CRS resulting from CAR T cell therapy, and given sufficient evidence of efficacy and an established safety profile for tocilizumab at the proposed dose, the benefits of tocilizumab outweigh the risks associated with remaining uncertainties. The benefit-risk profile of Actemra is considered favourable in the target patient population.
Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.