Regulatory Decision Summary for VENCLEXTA

Patients with chronic lymphocytic leukemia (CLL) who relapse after a short interval, or are refractory to previous therapies (R/R CLL), are a group of patients requiring new treatment options, particularly those who are older and/or have high-risk cytogenetic abnormalities (that is, 17p deletion [17p del]). Currently available treatment options for patients with R/R CLL with 17p del result in lower reported response rates (compared to patients without the 17p del) and no reported complete responses. Treatment for patients with R/R CLL without the 17p del also results in few complete responses, and treatment options are limited due to the safety profiles and tolerabilities of available drugs.

The clinical effectiveness of Venclexta in patients with CLL who have received at least one prior therapy is based primarily on an interim analysis of a single-arm Phase 2 study, and supported by interim data from a single-arm Phase 1 study. Both of these studies were performed in patients with R/R CLL, most of whom (118/164) were positive for the poor prognostic factor 17p del.

The interim analysis of the Phase 2 study resulted in an Independent Review Committee (IRC)-assessed overall response rate (ORR) of 79.4% (95% CI: 70.5, 86.6), with a complete response rate of 7.5%, in patients with R/R CLL with the 17p del. The IRC-assessed data from the interim analysis of the Phase 1 study was supportive, with an ORR of 73.7%, with complete responses in 7.0% of patients. Although there are limited data from patients who did not have the 17p deletion (n = 45), subgroup analysis of the patients enrolled in the Phase 1 study are supportive of Venclexta efficacy in patients who do not have the 17p del mutation (ORR = 75.6%, CR = 8.9%).

Overall, Venclexta demonstrated an acceptable safety profile in patients with R/R CLL. The most frequent adverse events were neutropenia, diarrhea, nausea, upper respiratory tract infection, and fatigue, with the most frequent serious adverse reactions being pneumonia, febrile neutropenia, and tumour lysis syndrome (TLS). The most frequently observed grade 3/4 events were TLS and neutropenia, which are both related to the on-target mechanism of action. Neutropenia was manageable through the use of dose interruptions and reductions, and no correlation was found between neutropenia and infections.

Tumor lysis syndrome is the most significant risk associated with Venclexta treatment in patients with R/R CLL during the first month of treatment (the dose ramp-up phase). Early in clinical development, TLS was reported in 13% of patients, which, in some cases, resulted in fatalities or kidney failure requiring dialysis. Protocol amendments implemented additional risk minimization measures for the ramp-up phase (including increased hydration and blood chemistry monitoring, treatment with anti-hyperuricemics, and hospitalization for some patients), which reduced the rate of TLS to 6%, all of which were cases of laboratory TLS. These TLS risk minimization measures are emphasized in the Venclexta Product Monograph, and are included as dosing recommendations to the prescribing physician. Furthermore, Venclexta is only available through specialty pharmacies and/or retail oncology pharmacies that are part of AbbVie’s managed distribution plan. Together, these measures are considered to adequately mitigate the risk of TLS.

A Risk Management Plan (RMP) for Venclexta was submitted by AbbVie Corporation to Health Canada. Upon review, the RMP was considered to be acceptable with revisions. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will put in place to minimize risks associated with the product.

Following review of the submission, Health Canada concluded that the submitted studies have provided promising evidence of clinical effectiveness and established an acceptable safety profile for the use of Venclexta in the treatment of patients with previously-treated CLL, a serious disease for which there is an unmet medical need. Confirmatory trials to verify its clinical benefit are required.

For more information on Health Canadas decision, please view the Summary Basis of Decision.