Summary Basis of Decision for Venclexta

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Venclexta is located below.

Recent Activity for Venclexta

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Venclexta

Updated:

2023-02-28

The following table describes post-authorization activity for Venclexta, a product which contains the medicinal ingredient venetoclax. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.

Drug Identification Numbers (DINs):

  • DIN 02458039 - 10 mg venetoclax, tablet, oral administration
  • DIN 02458047 - 50 mg venetoclax, tablet, oral administration
  • DIN 02458055 - 100 mg venetoclax, tablet, oral administration
  • DIN 02458063 - starter kit

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
SNDS # 253017 2021-05-21 Issued NOC 2022-04-11 Submission filed as a Level I – Supplement to update the PM with follow-up efficacy and safety data from studies MURANO/GO28667 and CLL14/BO25323. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions and Clinical Trials sections of the PM. An NOC was issued.
SNDS # 257218 2021-10-01 Cancellation Letter Received 2021-11-18 Submission filed as a Level I – Supplement to update the PM with the results of bioavailability study M20-070. Health Canada determined the study was not required to demonstrate interchangeability among marketed doses and requested the sponsor cancel the submission.
SNDS # 243474 2020-08-31 Issued NOC 2021-01-22 Submission filed as a Level II – Supplement (Safety) to update the PM with new safety information, and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Warnings and Precautions, Dosage and Administration sections of the PM, and corresponding changes were made to Part III: Patient Medication Information. An NOC was issued.
SNDS # 240541 2020-06-12 Issued NOC 2020-12-04 Submission filed as a Level I – Supplement for a new indication. The indication authorized was: in combination with azacitidine or low-dose cytarabine, for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) who are 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 240070 2020-05-29 Issued NOC 2020-11-24 Submission filed as a Level I – Supplement to add an alternate site for manufacturing of an intermediate. The data were reviewed and considered acceptable, and an NOC was issued.
SNDS # 234504 2019-12-16 Issued NOC 2020-09-15 Submission filed as a Level I – Supplement to update the PM with data from the study MURANO. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions and Clinical Trials sections of the PM. An NOC was issued.
SNDS # 228475 2019-06-07 Issued NOC 2020-04-28 Submission filed as a Level I – Supplement for a new indication. The indication authorized was: in combination with obinutuzumab, the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL). The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS # 234615 2019-12-18 Issued NOC 2020-02-18 Submission filed as a Level I – Supplement to revise the inner and outer labels for the 10 mg tablets. The submission was reviewed and considered acceptable, and an NOC was issued.
PBRER-C # 230703 2019-08-13 Filed 2020-02-11 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2018-12-05 to 2019-06-04. The information was reviewed and found acceptable. No further action was required.
SNDS-C # 224252 2019-01-31 Issued NOC
2020-01-13		 Submission filed as a Level I - Supplement in response to commitments made as per the provisions of the NOC/c Guidance. This SNDS-C was submitted to provide the final study report for the four Phase III confirmatory studies, and to update the PM with the data from these studies. Based on these data, this submission also requested the removal of the conditions from the NOC for this indication. The data continues to support an acceptable safety profile for the use of Venclexta, and together, the data support the favourable benefit/risk profile of Venclexta in the treatment of patients with CLL with 17p deletion who have received at least one prior therapy, or patients with CLL without the 17p deletion who have received at least one prior therapy and for whom there are no other available treatment options. The data were reviewed and considered acceptable. Appropriate changes were made to the PM. As a result of the submission, the conditions were removed from the NOC that had been issued 2016-09-30.
SNDS # 224188 2019-01-29 Issued NOC
2019-10-30		 Submission filed as a Level I - Supplement to update the PM with dosing recommendations for patients with severe hepatic impairment. As a result of the submission, the following sections of the PM were updated: Warnings and Precautions, and Dosage and Administration. The benefit/risk profile for Venclexta remains positive when used for its approved indication. The submission was reviewed and considered acceptable, and an NOC was issued.
NC # 230973 2019-08-21 Issued NOC
2018-07-17		 Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Serious Warnings and Precautions Box, and Warnings and Precautions sections of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
PBRER-C # 219062 2018-08-09 Filed
2019-08-19		 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2017-12-05 to 2018-06-04. The information was reviewed and found acceptable.
SNDS # 215852 2018-04-30 Issued NOC
2019-02-18		 Submission filed as a Level I - Supplement to update the PM regarding azithromycin and Venclexta, a P-glycoprotein substrate. As a result of the SNDS, modifications were made to the Drug Interactions section of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOC was issued.
SNDS-C # 222815 2018-12-07 Cancellation Letter received
2019-01-24		 Submission filed as a Level I - Supplement in response to commitments made as per the provisions of the NOC/c Guidance. This SNDS-C was submitted to provide the final study report for the confirmatory studies and to update the PM. The sponsor cancelled the SNDS-C.
SNDS # 214078 2018-02-28 Issued NOC
2018-09-21		 Submission filed as a Level I - Supplement to add a new indication for Venclexta. The indication authorized was Venclexta in combination with rituximab for the treatment of adult patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. Regulatory Decision Summary published.
NC # 214135 2018-03-01 Issued NOL
2018-07-17		 The submission was filed as a Level II (90 day) Notifiable Change to update the PM. As a result of the NC, modifications were made to the Drug Interactions section of the PM, and corresponding changes were made to the PM Part III: Patient Medication Information. The submission was reviewed and considered acceptable, and an NOL was issued.
SNDS # 215771 2018-04-26 Issued NOC
2018-06-11		 Submission filed as a Level I - Supplement to update the carton label and package insert. The submission was reviewed and considered acceptable, and an NOC was issued.
PBRER-C # 213574 2018-02-08 Filed 2018-03-22 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2017-06-05 to 2017-12-04. The information was reviewed and found acceptable.
PBRER-C # 208365 2017-08-10 Filed
2018-02-26		 Submission filed in response to commitments made as per the provisions of the NOC/c Guidance. PBRER-C for the period 2016-12-05 to 2017-06-04. The information was reviewed and found acceptable.
Drug product (DINs 02458039, 02458047, 02458055, 02458063) market notification Not applicable Date of first sale:
2016-10-31		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 190761 2015-12-15 Issued NOC, under NOC/c Guidance
2016-09-30		 Notice of Compliance issued under the NOC/c Guidance for New Drug Submission.
Summary Basis of Decision (SBD) for Venclexta

Date SBD issued: 2016-12-22

The following information relates to the new drug submission for Venclexta.

Venetoclax, 10 mg, 50 mg and 100 mg venetoclax, tablets, oral

Drug Identification Number (DIN):

  • 02458039 - 10 mg tablet
  • 02458047 - 50 mg tablet
  • 02458055 - 100 mg tablet
  • 02458063 - starter kit

AbbVie Corporation

New Drug Submission Control Number: 190761

 

On September 30, 2016, Health Canada issued a Notice of Compliance under the Notice of Compliance with Conditions (NOC/c) Guidance to AbbVie Corporation for the drug product Venclexta. The product was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit. Patients should be advised of the fact that the market authorization was issued with conditions.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Venclexta is favourable as monotherapy for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least one prior therapy, or patients with CLL without 17p deletion who have received at least one prior therapy and for whom there are no other available treatment options. Clinical effectiveness of Venclexta is based on response rate results from interim analyses of single-arm studies. Clinical trial data in patients who do not harbour the 17p deletion are limited.

1 What was approved?

Venclexta, an antineoplastic agent, was authorized as monotherapy for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least one prior therapy, or patients with CLL without 17p deletion who have received at least one prior therapy and for whom there are no other available treatment options.

Clinical effectiveness of Venclexta is based on response rate results from interim analyses of single-arm studies. Clinical trial data in patients who do not harbour the 17p deletion are limited.

Venclexta is only available through specialty pharmacies and/or retail oncology pharmacies that are part of AbbVie's managed distribution program.

No overall differences in safety or effectiveness were observed between older (aged ≥65 years) and younger patients. No specific dose adjustment is required for elderly patients (aged ≥65 years).

No safety and efficacy data for Venclexta in children and adolescents below 18 years of age are available.

Venclexta is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Furthermore, concomitant use of Venclexta with strong cytochrome P450 (CYP) 3A inhibitors at initiation and during ramp-up phase is contraindicated.

Venclexta was approved for use under the conditions stated in the Venclexta Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Venclexta (10 mg, 50 mg, and 100 mg venetoclax) is presented as a tablet. In addition to the medicinal ingredient, each tablet contains the following non-medicinal ingredients: calcium phosphate dibasic, colloidal silicon dioxide, copovidone, iron oxide yellow, polyethylene glycol, polysorbate 80, polyvinyl alcohol, sodium stearyl fumarate, talc, and titanium dioxide. Each 50 mg tablet also contains iron oxide black and iron oxide red.

For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Venclexta Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Venclexta approved?

Health Canada considers that the benefit/risk profile is favourable for Venclexta as monotherapy for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least one prior therapy, or patients with CLL without 17p deletion who have received at least one prior therapy and for whom there are no other available treatment options. Venclexta was authorized under the NOC/c Guidance on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit.

Chronic lymphocytic leukemia (CLL) is a monoclonal disorder characterized by a progressive accumulation of functionally incompetent lymphocytes. It is an incurable disease, with most patients relapsing following initial therapy, and becoming increasingly resistant or refractory to subsequent treatment with diminished response rates and response durations. In particular, patients with deletions in the short arm of chromosome 17 (17p deletion) have an increased risk of relapse and death. While only a minority of patients with CLL have 17p deletion at the time of diagnosis, the proportion increases with successive chemotherapy treatments. Between 30% and 50% of relapsed CLL patients harbour 17p deletion. The median life expectancy of these patients is 2 to 3 years from first-line treatment, and no standard treatment exists for this patient group.

Venetoclax, the medicinal ingredient of Venclexta, is an orally bioavailable small-molecule inhibitor of B-cell lymphoma (BCL)-2, an anti-apoptotic protein that inhibits programmed cell death (apoptosis). Overexpression of BCL-2 in various hematologic malignancies contributes to cancer cell survival by binding and sequestering high levels of BH3 motif-containing pro-apoptotic proteins, and has been associated with resistance to chemotherapeutics. Venetoclax binds to the BH3-binding groove of BCL-2, displacing pro-apoptotic proteins like BIM to initiate mitochondrial outer membrane permeabilization, the release of cytochrome c, and caspase activation, ultimately resulting in programmed cell death (apoptosis) of the cancer cells. In non-clinical studies, venetoclax has demonstrated cytotoxic activity towards tumour cells derived from B-cell and other hematologic malignancies.

The market authorization with conditions of Venclexta was based primarily on an interim analysis of a single-arm Phase II study, and supported by interim data from a single-arm Phase I study. The assessment of efficacy of Venclexta monotherapy relied on these two studies, which were performed in 164 patients with relapsed or refractory CLL, 118 of whom were positive for the poor prognostic factor, 17p deletion. The interim analysis of the Phase II 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 (CR) rate of 7.5%, in patients with relapsed/refractory CLL with the 17p deletion. The IRC-assessed data from the interim analysis of the Phase I study were supportive, with an ORR of 74% (95% CI: 60; 85), with CRs in 7% of patients. Although there are limited data from patients who did not have the 17p deletion, the Phase I study included 45 patients with CLL without this mutation. The subgroup analysis of these patients was supportive of Venclexta efficacy in patients who do not have the 17p deletion (ORR = 76%, CR = 9%). In order to confirm the efficacy of the product, results from confirmatory studies will be submitted for evaluation to Health Canada as part of the post-approval commitments (see What follow-up measures will the company take?).

The most frequent adverse events included neutropenia, diarrhea, nausea, upper respiratory tract infection, and fatigue, while the most frequent serious adverse reactions were pneumonia, febrile neutropenia, and tumour lysis syndrome (TLS). The most frequently observed Grade 3/4 events were neutropenia, anemia, thrombocytopenia, neutrophil count decreased, febrile neutropenia, and pneumonia. Neutropenia was manageable with the use of granulocyte colony-stimulating factor (G-CSF) and also through the dose interruptions and reductions. No correlation was found between neutropenia and infections.

Tumour lysis syndrome (TLS) was the most significant risk associated with Venclexta treatment in patients with relapsed/refractory 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. Subsequent 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 risk minimization measures, in addition to a managed distribution program for Venclexta, are considered to adequately mitigate the risk of TLS. A Serious Warnings and Precautions box in the Venclexta Product Monograph highlights TLS as a significant adverse drug reaction identified in clinical trials conducted with Venclexta and specifies that patients must receive prophylaxis for TLS, including hydration and anti-hyperuricemics prior to initiating treatment. The requirement for weekly dosage ramp-up and blood chemistry monitoring is also included in the Serious Warnings and Precautions box of the Venclexta Product Monograph.

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

A Look-alike Sound-alike brand name assessment was performed and the proposed name Venclexta was accepted.

Overall, the therapeutic benefits seen in the pivotal study are promising and the benefits of Venclexta therapy are considered to outweigh the potential risks of the treatment of patients with previously-treated CLL, a serious disease for which there is an unmet medical need. Venclexta has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling, adequate monitoring, and managed distribution of Venclexta. Appropriate warnings and precautions are in place in the Venclexta Product Monograph to address the identified safety concerns. As described within the framework of the NOC/c Guidance, safety monitoring on the use of Venclexta will be ongoing. Further evaluation will take place upon the submission of the complete study reports for the final analysis of the requested confirmatory studies.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Venclexta?

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 Venclexta. An assessment was conducted and it was determined there was promising evidence of clinical effectiveness of Venclexta for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least one prior therapy, or patients with CLL without the 17p deletion who have received at least one prior therapy and for whom there are no other available treatment options.

Submission Milestones: Venclexta

Submission Milestone Date
Pre-submission meeting: 2015-10-15
Submission filed: 2015-12-18
Screening  
Screening Deficiency Notice issued: 2016-01-22
Response filed: 2016-01-29
Screening Acceptance Letter issued: 2016-02-03
Review  
Biopharmaceutics Evaluation complete: 2016-06-01
Quality Evaluation complete: 2016-07-11
Clinical Evaluation complete: 2016-08-12
Labelling Review complete: 2016-08-07
Notice of Compliance with Conditions Qualifying Notice (NOC/c-QN) issued: 2016-08-18
Review of Response to NOC/c-QN:  
Response filed (Letter of Undertaking): 2016-08-30
Clinical Evaluation complete: 2016-09-27
Labelling Review complete: 2016-09-26
Notice of Compliance (NOC) issued by Director General, Therapeutic Products Directorate under the Notice of Compliance with Conditions (NOC/c) Guidance: 2016-09-30

The Canadian regulatory decision on the non-clinical and clinical review (with the exception of the review of human pharmacodynamics studies) of Venclexta was based on a critical assessment of the Canadian data package. The foreign review completed by the United States Food and Drug Administration (FDA) was used as an added reference. The Canadian regulatory decision on the review of the human pharmacodynamics studies was based on the United States FDA review, referring to the data filed in Canada as necessary.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4 What follow-up measures will the company take?

In addition to requirements outlined in the Food and Drugs Act and Regulations, and in keeping with the provisions outlined in the Notice of Compliance with Conditions (NOC/c) Guidance, the sponsor has agreed to provide the complete study reports for the final analyses of the following confirmatory studies:

  • Study M13-982: A Phase II open-label study of the efficacy of ABT-199 (GDC-0199) in subjects with relapsed/refractory or previously untreated chronic lymphocytic leukemia (CLL) harbouring the 17p deletion.
  • Study M12-175: A Phase I study evaluating the safety and pharmacokinetics of ABT-199 in subjects with relapsed or refractory CLL and non-Hodgkin’s lymphoma.
  • Study M14-032: A Phase II open-label study of the efficacy and safety of ABT-199 (GDC-0199) in CLL subjects with relapse or refractory to B-cell receptor signaling pathway inhibitor therapy.
  • Study GO28667 (MURANO): A multicentre, Phase III, open-label, randomized study in relapsed/refractory patients with CLL to evaluate the benefits of GDC-0199 (ABT-199) plus rituximab compared with bendamustine plus rituximab.

The sponsor has also agreed to provide Health Canada with the following post-market safety monitoring information:

  • Report(s) of all serious adverse drug reactions (ADRs) that occur in Canada and all serious unexpected ADRs that occur outside of Canada, within 15 days, in accordance with the current Food and Drug Regulations (C.01.017) and guidance documents.
  • Conclusions from the analysis of AbbVie’s Annual Safety Summary Reports, in a manner deemed consistent with the current Notice of Compliance with Conditions (NOC/c) Guidance.
5 What post-authorization activity has taken place for Venclexta?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada’s decision was negative or positive. The PAAT will continue to be updated during the product’s life cycle.

The PAAT for Venclexta is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

Clinical Pharmacology

Venetoclax, the medicinal ingredient of Venclexta, is an orally bioavailable small-molecule inhibitor of B-cell lymphoma (BCL)-2, an anti-apoptotic protein. Venetoclax binds to the BH3-binding groove of BCL-2, displacing pro-apoptotic proteins like BIM to initiate mitochondrial outer membrane permeabilization, the release of cytochrome c, and caspase activation, ultimately resulting in programmed cell death (apoptosis) of the cancer cells.

The pharmacokinetics of venetoclax was characterized in patients with relapsed and refractory CLL or non-Hodgkin’s lymphoma. Steady state is achieved by 6 weeks of daily dosing. Venetoclax steady-state area under the curve (AUC) increased proportionally across the dose range of 150 mg to 800 mg.

The effect of food on venetoclax exposure was evaluated in healthy volunteers. Administration with a low-fat meal increased venetoclax exposure by approximately 3-fold and administration with a high-fat meal increased venetoclax exposure by 5-fold compared to fasting conditions. Venetoclax should be administered with a meal.

Venetoclax is metabolized predominantly by cytochrome P450 (CYP) 3A. Co-administration of CYP3A inhibitor ketoconazole resulted in a 2.3-fold and 6.4-fold increase in venetoclax maximum plasma concentration (Cmax) and AUC, respectively. Multiple doses of CYP3A inducer rifampicin decreased venetoclax Cmax and AUC by 42% and 71%, respectively. In addition, venetoclax is a P-glycoprotein (P-gp) substrate. Single dose co-administration of the P-gp inhibitor rifampicin resulted in increased venetoclax Cmax and AUC by 106% and 78%, respectively. Venetoclax is also an inhibitor of P-gp and breast cancer resistance protein (BCRP) efflux transporter.

Venetoclax is nearly entirely eliminated by hepatic metabolism. Population pharmacokinetic analysis indicates that mild to moderate hepatic impairment or mild to moderate renal impairment has no impact on the venetoclax clearance. A dedicated clinical trial has not been conducted with venetoclax in patients with moderate or severe hepatic impairment or severe renal impairment.

In order to mitigate the risk of high venetoclax exposure, the Venclexta Product Monograph specifically addresses the concomitant use of Venclexta with CYP3A inhibitors or P-gp inhibitors. Moreover, concomitant use of Venclexta with strong CYP3A inhibitors at initiation and during ramp-up phase is contraindicated.

Overall, the data from the submitted clinical pharmacology studies are considered sufficient to support the marketing authorization of Venclexta for the specified indication.

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

Clinical Efficacy

The clinical efficacy of Venclexta was demonstrated primarily in the interim analysis data from an ongoing Phase II open-label, single-arm clinical study (Study M13-982) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) harbouring the 17p deletion that includes the TP53 locus. In addition, supporting efficacy data were derived from an interim analysis of a Phase I dose escalation study in patients with relapsed or refractory CLL (Study M12-175).

Study M13-982

The efficacy population of the Phase II study (M13-982) included 107 patients with CLL with 17p deletion mutation who had received at least one prior therapy. The patients received Venclexta monotherapy via a weekly ramp-up schedule starting at 20 mg and ramping to 50 mg, 100 mg, 200 mg and 400 mg daily, with median treatment duration of 12.1 months. The primary efficacy endpoint was overall response rate (ORR), as assessed by an independent review committee (IRC) using the International Workshop for CLL Guidelines updated by the National Cancer Institute-sponsored Working Group on CLL (2008).

The primary efficacy endpoint of IRC-assessed ORR was 79.4% (95% CI: 70.5; 86.6). The investigator-assessed data were consistent, with the ORR determined to be 73.8% (95% CI: 64.4; 81.9). The IRC-assessed ORR results were consistent across all analyzed subgroups, including those with known negative prognostic indicators (for example [e.g.], ≥3 prior therapies, lymph nodes ≥5 cm, and fludarabine refractory disease).

Complete response (CR), including CR with incomplete bone marrow recovery (CRi), was assessed as a secondary endpoint. The IRC-assessed CR+CRi rate was determined to be 7.5%.

Minimal residual disease was evaluated in patients who achieved CR, CRi, or partial remission (PR) with limited remaining disease with Venclexta treatment. Minimal residual disease-negative status was defined as no detectable CLL cells at a sensitivity of 10-4. Seventeen percent (18/107) of patients were minimal residual disease-negative in the peripheral blood, including 6 patients who were also minimal residual disease-negative in the bone marrow.

Study M12-175

The supportive Phase I study, M12-175, restricted enrollment to patients with relapsed/refractory CLL for whom no other therapies were available. It provided efficacy data from 57 patients with relapsed/refractory CLL (45 of whom did not have the 17p deletion) who received 400 mg Venclexta for a median treatment duration of 11.5 months. This study was designed primarily to assess the safety of venetoclax and to determine the recommended Phase II dose, and was the primary source of efficacy data for patients without the 17p deletion.

The IRC-assessed ORR was determined to be 74% (95% CI: 60; 85), with CR+CRi in 7% of these patients. Subgroup analysis for non-17p deletion patients (number of patients [n] = 45) showed an IRC-assessed ORR of 76% (95% CI: 61; 87), with CR+CRi of 9%.

Indication

The original New Drug Submission for Venclexta was filed with the following proposed indication:

Venclexta (venetoclax) is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy; this includes patients with 17p deletion.

Health Canada revised the proposed indication in order to more accurately reflect the different restrictions of use for the two subgroups of patients with CLL (those with 17p deletion, and those without). A caveat statement was also added to the indication, providing additional details regarding the limitations of the currently available data. In addition, a statement was added specifying that Venclexta is only available through a managed distribution program. Accordingly, Health Canada approved the following indication:

Venclexta (venetoclax) is indicated as monotherapy for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least one prior therapy, or patients with CLL without 17p deletion who have received at least one prior therapy and for whom there are no other available treatment options.

Clinical effectiveness of Venclexta is based on response rates results from interim analyses of single-arm studies. Clinical trial data in patients who do not harbour the 17p deletion are limited.

Venclexta is only available through specialty pharmacies and/or retail oncology pharmacies that are part of AbbVie's managed distribution program.

For more information, refer to the Venclexta Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Venclexta in patients with relapsed/refractory CLL was evaluated in a total of 553 patients who received at least one dose of Venclexta. This safety population included CLL patients in ongoing clinical studies. Of those, a total of 289 patients were treated with Venclexta monotherapy (all doses). There was also a safety analysis of a pooled dataset of patients with relapsed/refractory CLL treated with Venclexta 400 mg monotherapy, with a median exposure of 10.3 months (All 400 mg Safety Analysis Set, n = 240). Many of those patients were still undergoing Venclexta treatment at the time of the interim analysis. 

The size of the safety database is considered to be acceptable for the assessment of Venclexta safety in the target population; however, all data stem from single-arm trials. The single-arm trial design, combined with the characteristics of patients with relapsed/refractory CLL (that is [i.e.], frequently elderly, with comorbidities and concomitant medications), makes it difficult to distinguish adverse events that may be due to Venclexta from events due to other causes in these patients.

The most common adverse events, reported in more than 20% of patients, were neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia and fatigue.

The most common serious adverse reactions were pneumonia, febrile neutropenia, and tumour lysis syndrome, while the most frequent causes of Venclexta discontinuation were diarrhea, nausea, and increased blood creatinine.

Tumour lysis syndrome (TLS) is the most significant adverse reaction identified in Venclexta-treated patients, and resulted in fatalities early in the clinical development of Venclexta. In order to reduce the risk of TLS, protocol amendments were implemented, which included an adjustment to the dosage schedule to include a ramp-up phase, TLS risk assessment based on baseline lymph node size and absolute lymphocyte count, and increased prophylaxis measures, such as hydration guidelines, use of anti-hyperuricemics, and close laboratory monitoring. Upon implementation of these extensive measures, the rate of TLS decreased from 13% (which included 2 fatal events, and 3 events of acute renal failure, 1 requiring dialysis) in the pre-amendment protocol to 6%, with no events of clinical TLS (only laboratory TLS) in the post-amendment protocol. These data demonstrate that the risk of TLS is manageable; however, it is important for risk mitigation measures to be employed for all patients. The Serious Warnings and Precautions box of the Venclexta Product Monograph contains details pertaining to TLS. Furthermore, the Dosage and Administration section of the Venclexta Product Monograph provides clear recommendations regarding hospitalization, monitoring and TLS prohylaxis during the ramp-up phase. In order to ensure patient monitoring recommendations are followed, a managed distribution program for Venclexta is also required. Abbvie will only distribute Venclexta through a Speciality Health Network or retail oncology pharmacies that are part of AbbVie’s managed distribution program.

Neutropenia, another significant adverse event, may be due to both the underlying disease as well as Venclexta administration. Due to comorbidities and confounding factors, it is not possible to determine the frequency of neutropenia related directly to Venclexta; however, it was frequently reported in all Venclexta clinical studies. In the All 400 mg Analysis Set, neutropenia was reported in 45% of patients. Grade 3/4 neutropenia was reported in 41% of patients, with febrile neutropenia reported as a serious adverse event in 5% of patients. There were no patients who discontinued Venclexta therapy due to neutropenia, and there was no correlation found between rates of neutropenia and infection.

Infections were also reported in Venclexta clinical studies. Similarly to neutropenia, given the underlying disease and other comorbidities, it is difficult to determine a causal relationship between infections and Venclexta administration. Infections were reported in 65.4% of the All 400 mg Safety Analysis Set, with Grade 3/4 infections in 18% of patients. In the same analysis set, infections were reported as serious adverse events in 18% of patients. Infections were considered by the investigator to have a “reasonable possibility of being related to Venclexta” in 16% of patients.

Second primary malignancies, most frequently skin cancers, were reported in 12% of patients, including non-melanoma skin cancers in 8% of patients, and non-skin related malignancies in 4% of patients. Causality with Venclexta has not been established.

The safety profile of Venclexta was consistent between the All 400 mg Safety Analysis Set (n = 240), and the 17p deletion subgroup (n = 160).

The submitted studies have demonstrated an acceptable safety profile for the use of Venclexta in the treatments of patients with relapsed or refractory CLL.

For more information, refer to the Venclexta Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

The non-clinical pharmacology and toxicology studies support the use of Venclexta for the specified indication.

Venetoclax, the medicinal ingredient of Venclexta, binds to the anti-apoptotic protein BCL-2, resulting in the death of cells that are dependent on BCL-2 overexpression. Treatment of leukemia cells with venetoclax induced the hallmarks of apoptosis (e.g., cytochrome c release from the mitochondria, caspase activation, and externalization of phosphatidyl-serine in a dose-dependent manner). Following treatment with venetoclax, potent cell death occurred in most human-derived cancer cell lines with BCL-2 overexpression.

The primary toxicities associated with repeat-dose administration of venetoclax were effects on the hematologic system (decreased lymphocytes and red blood cell mass) in mice and dogs, and the male reproductive system (non-reversible testicular germ cell depletion) in dogs. These effects were expected based on the on-target pharmacological inhibition of BCL-2. Other noteworthy findings observed in dogs, but not in mice, were single-cell necrosis in multiple tissues and hair coat color change.

Carcinogenicity studies have not been conducted with venetoclax. In vitro, venetoclax was non-mutagenic and did not induce numerical or structural chromosomal aberrations. Venetoclax was also non-clastogenic in an in vivo mouse bone marrow micronucleus assay.

In female mice, there were no venetoclax-related effects on estrous cycling, mating and fertility. Similarly, in male mice, there were no venetoclax-related effects on male mating and fertility parameters. However, venetoclax produced adverse, non-dose related, irreversible microscopic findings of testicular germ cell depletion in dogs. Based on these findings, male fertility may be compromised by treatment with Venclexta.

In embryo-fetal development studies, venetoclax treatment of pregnant mice during the period of organogenesis resulted in an increase in postimplantation loss, reduced fetal body weights, an increase in the average number of early resorptions and in the percentage of dead or resorbed conceptuses per litter. Venetoclax may cause fetal harm if administered to pregnant women.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Venclexta Product Monograph. In view of the intended use of Venclexta, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

Appropriate warnings and precautionary measures are in place in the Venclexta Product Monograph to address the identified safety concerns.

For more information, refer to the Venclexta Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.3 Quality Basis for Decision

The Chemistry and Manufacturing information submitted for Venclexta has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 24 months is considered to be acceptable for Venetoclax tablets when stored at temperature between 2ºC and 30ºC.

Proposed limits of drug-related impurities are considered adequately qualified, i.e., within International Council for Harmonisation (ICH) limits and/or qualified from toxicological studies.

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

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