Regulatory Decision Summary for Carvykti

The purpose of this New Drug Submission (NDS) was to gain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, for Carvykti, submitted by Janssen Inc.

This New Drug Submission was filed to obtain market authorization for the following indication:

“Carvykti (ciltacabtagene autoleucel) is a B-cell maturation antigen (BCMA)-directed genetically

modified autologous T-cell immunotherapy indicated for the treatment of patients with relapsed or refractory multiple myeloma, who have received at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody.”

Upon review, the approved indication was:

“Carvykti (ciltacabtagene autoleucel) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous Tcell immunotherapy indicated for the treatment of adult patients with multiple myeloma, who have received at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody, and who are refractory to their last treatment.”

The sponsor filed a request for Advance Consideration under the Notice of Compliance with Conditions (NOC/c) Guidance for the review of the New Drug Submission (NDS) for Carvykti for the treatment of adult patients with multiple myeloma. Carvykti is an immunotherapy that consists of autologous T cells genetically modified to express a chimeric antigen receptor (CAR).

After evaluation of the submitted data package, Health Canada authorized with conditions, Carvykti, for the treatment of adult patients with multiple myeloma, who have received at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 antibody, and who are refractory to their last treatment.

The authorization of Carvykti was based on the results of an open-label single-arm study designed to evaluate the efficacy and safety of Carvykti in patients with relapsed and refractory multiple myeloma. A total of 113 subjects were enrolled (apheresed), out of which 101 subjects received conditioning regimen and 97 subjects received a single-dose Carvykti infusion.

The recommended dose of Carvykti is 0.5-1.0 x 10⁶ CAR-positive viable T-cells per kg of body weight, with a maximum dose of 1 x 10⁸ CAR-positive viable T-cells per single infusion.

The primary efficacy endpoint was overall response rate (ORR), defined as the proportion of subjects who achieved a partial response (PR) or better. The ORR was 97.9% for the All Treated population (N = 97) and 84.1% for the All Enrolled population (N = 113) based on the available data up to the 11 February 2021 cut-off date, which represents a median treatment duration of 18.0 months.

The safety profile of Carvykti is similar to other authorized CAR T-cell therapies and includes serious adverse reactions, such as cytokine release syndrome (CRS), hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) and other neurotoxicities. Other important safety concerns associated with Carvykti infusion include hypogammaglobulinemia (increased risk of infection), infections (including fatalities), viral reactivations, and prolonged and recurrent cytopenias. Cytopenias, common following lymphodepletion and CAR-T therapy, were reported for all subjects.

Overall, the benefit-risk profile is considered positive when Carvykti is administered at qualified treatment centres where the risks of this therapy can be properly monitored and managed. Carvykti is considered a promising treatment option for multiple myeloma patients who have received multiple prior therapies, with confirmation of benefit and longer-term safety to be provided from the final results of the Phase 1b/2 and Phase 3 clinical trials.

An updated Risk Management Plan (RMP) for Carvykti was reviewed by Health Canada and considered acceptable.

The chemistry and manufacturing information submitted for Carvykti has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

Following review and requested revisions, the final labelling and Product Monograph were considered to be acceptable.

A Notice of Compliance with Conditions (NOC/c) was recommended.

The following conditions were issued:

Confirmatory Studies

• The report of the final analysis of the study entitled A phase 1b-2, open-label study of JNJ-68284528, a Chimeric Antigen Receptor T cell (CAR-T) therapy directed against BCMA in subjects with relapsed or refractory multiple myeloma. The timelines should be included in the Letter of Undertaking, including the earliest anticipated availability of the data to be filed as a Supplement to a New Drug Submission (SNDS)-confirmatory (SNDS-c).

• The report of the final analysis of the study entitled A phase 3 randomised study comparing JNJ-68284528, a CAR-T therapy directed against BCMA versus Pomalidomide + Bortezomib + Dexamethasone (PVd) or Daratumumab + Pomalidomide + Dexamethasone (DPd) in subjects with relapsed and lenalidomiderefractory multiple myeloma. The timelines should be included in the Letter of Undertaking, including the earliest anticipated availability of the data to be filed as a Supplement to a New Drug Submission (SNDS)-confirmatory (SNDS-c).

For further details about Carvykti, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.