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Pronunciation | /vɛˈnɛtəklæks/ ve-NE-tə-klaks |
Trade names | Venclexta, Venclyxto |
Other names | GDC-0199, ABT-199, RG-7601 |
AHFS/Drugs.com | Monograph |
MedlinePlus | a616028 |
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Routes of administration | By mouth |
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Pharmacokinetic data | |
Protein binding | >99.9% [5] |
Metabolism | Liver (CYP3A4, CYP3A5) |
Elimination half-life | ~26 hours |
Excretion | Feces (>99.9%; 20.8% as unchanged venetoclax) |
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PDB ligand | |
CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.254.611 |
Chemical and physical data | |
Formula | C45H50ClN7O7S |
Molar mass | 868.45 g·mol−1 |
3D model (JSmol) | |
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Venetoclax, sold under the brand names Venclexta and Venclyxto, is a medication used to treat adults with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or acute myeloid leukemia (AML). [5] [6]
The most common side effects are low levels of neutrophils (a type of white blood cell), diarrhea, nausea, anemia (low red blood cell counts), nose and throat infection and tiredness. [6]
Venetoclax attaches to a protein called Bcl-2. [6] This protein is present in high amounts in CLL cancer cells, where it helps the cells survive for longer in the body and makes them resistant to cancer medicines. [6] By attaching to Bcl-2 and blocking its actions, venetoclax causes the death of cancer cells and thereby slows down progression of the disease. [6]
In the US, venetoclax is indicated for adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). [5] [7] Indication does not depend on mutation status (e. g. 17p deletion, IGHV mutation, 12+).
In the EU, venetoclax monotherapy is indicated for the treatment of chronic lymphocytic leukemia (CLL) in the presence of 17p deletion or TP53 mutation in adults who are unsuitable for or have failed a B cell receptor pathway inhibitor and for the treatment of CLL in the absence of 17p deletion or TP53 mutation in adults who have failed both chemoimmunotherapy and a B cell receptor pathway inhibitor. [6]
Venetoclax is also indicated as part of a combination therapy for acute myeloid leukemia (AML). [5] For this purpose it is used with azacitidine, decitabine, or low-dose cytarabine for newly diagnosed adults who are age 75 years or older, or those with other health problems where intensive chemotherapy cannot be used. [5]
Common side effects of venetoclax include neutropenia (low white blood cell count), nausea, anemia, diarrhea, upper respiratory tract infection, fatigue, and thrombocytopenia (low platelet count). Major side effects include tumor lysis syndrome and severe neutropenia. Additionally, this drug may cause fertility problems in males. [5]
Venetoclax is a BH3-mimetic. [8] Venetoclax blocks the anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein, leading to programmed cell death of CLL cells. Overexpression of Bcl-2 in some lymphoid malignancies has been linked to increased resistance to chemotherapy. [9]
The maximum plasma concentration achieved after oral administration occurred 5–8 hours after dose. [5] Steady state maximum concentration with low-fat meal conditions at the 400 mg once daily dose was found to be 2.1 ± 1.1 μg/mL. It is recommended that venetoclax be administered with a meal. [5]
The apparent volume of distribution for venetoclax is approximately 256–321 L. It is highly bound to human plasma protein. Within a concentration range of 1-30 μM (0.87-26 μg/mL), the fraction unbound in plasma was less than 0.01. [5]
Venetoclax is metabolized by CYP3A4/5 as proven by in-vitro studies. [5] Those using the drug should not consume grapefruit products because they contain CYP3A inhibitors. [5] Additionally, while using venetoclax it is not recommended to use other drugs which contain CYP3A inhibitors (i.e.: erythromycin, ciprofloxacin, diltiazem, dronedarone, fluconazole, verapamil). [5] Venetoclax is excreted from the body via the fecal route. [5]
In 2015, the United States Food and Drug Administration (FDA) granted the breakthrough therapy designation to venetoclax for people with CLL or SLL who have relapsed, become intolerant to, or refractory to previous treatment.[ medical citation needed ]
In April 2016, the FDA approved venetoclax for use in those with CLL who have 17p deletion (deletion located on the chromosome 17 short arm) and who have been treated with at least one prior therapy. [10] [11] [12] [13] Based on overall response rate, the indication was approved under accelerated FDA approval. [5]
The efficacy of venetoclax was tested in a single-arm clinical trial of 106 participants with CLL who have a 17p deletion and who had received at least one prior therapy. [11] Trial participants took venetoclax orally every day, beginning with 20 mg and increasing over a five-week period to 400 mg. [11] Results showed that 80 percent of trial participants experienced a complete or partial remission of their cancer. [11] The trial was conducted in the US, Canada, France, Germany, Poland, the United Kingdom, and Australia. [13]
The application for venetoclax was granted priority review and accelerated approval along with breakthrough therapy designation and orphan drug designation. [11]
Venetoclax was approved for use in the European Union in December 2016. [6]
In June 2018, the FDA granted regular approval to venetoclax for people with CLL or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy. [14]
Approval was based on MURANO (NCT02005471), a randomized (1:1), multicenter, open-label trial of venetoclax with rituximab (VEN+R) versus bendamustine with rituximab (B+R) in 389 participants with CLL who had received at least one prior line of therapy. [14] Participants in the VEN+R arm completed a 5-week ramp-up venetoclax schedule and then received venetoclax 400 mg once daily for 24 months measured from the rituximab start date. [14] Rituximab was initiated after venetoclax ramp-up and given for 6 cycles (375 mg/m2 intravenously on cycle 1 day 1 and 500 mg/m2 intravenously on day 1 of cycles 2–6, with a 28-day cycle length). [14] The comparator arm received 6 cycles of B+R (bendamustine 70 mg/m2 on days 1 and 2 of each 28-day cycle and rituximab at the above described dose and schedule). [14]
The application for venetoclax in combination with rituximab was granted priority review along with a breakthrough therapy designation. [14]
In November 2018, in the United States, venetoclax was approved in combination with azacitidine or decitabine or low-dose cytarabine for the treatment of newly diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. [15]
Accelerated approval was based on two open-label non-randomized trials in participants with newly diagnosed AML who were >= 75 years of age or had comorbidities that precluded the use of intensive induction chemotherapy. [15] Efficacy was established based on the rate of complete remission (CR) and CR duration. [15]
Study M14-358 (NCT02203773) was a non-randomized, open-label clinical trial of venetoclax in combination with azacitidine (n=67) or decitabine (n=13) in newly diagnosed participants with AML. [15] In combination with azacitidine, 25 participants achieved a CR (37%, 95% CI: 26, 50) with a median observed time in remission of 5.5 months (range: 0.4–30 months). [15] In combination with decitabine, 7 participants achieved a CR (54%, 95% CI: 25, 81) with a median observed time in remission of 4.7 months (range: 1.0–18 months). [15] The observed time in remission is the time from start of CR to data cut-off date or relapse from CR. [15] In a phase 3 study of azacitidine and venetoclax in untreated acute myeloid leukemia not eligible for standard induction chemotherapy, the addition of venetoclax to azacitidine resulted in an improvement in median overall survival (14.7 months versus 9.6 months) and improved complete remission rates. [16]
Study M14-387 (NCT02287233) was a non-randomized, open-label trial of venetoclax in combination with low-dose cytarabine (n=61) in newly diagnosed participants with AML, including participants with previous exposure to a hypomethylating agent for an antecedent hematologic disorder. [15] In combination with low-dose cytarabine, 13 participants achieved a CR (21%, 95% CI: 12, 34) with a median observed time in remission of 6 months (range: 0.03–25 months). [15]
In May 2019, the label was extended by accelerated approval to include all adults with CLL/SLL disregarding prior treatment or mutation status. [7]
Approval was based on CLL14 (NCT02242942), a randomized (1:1), multicenter, open label, actively controlled trial of venetoclax in combination with obinutuzumab (VEN+G) versus obinutuzumab in combination with chlorambucil (GClb) in 432 participants with previously untreated CLL with coexisting medical conditions. [7]
The major efficacy outcome was progression-free survival (PFS) assessed by an independent review committee. [7] The trial demonstrated a statistically significant improvement in PFS for participants who received VEN+G compared with those who received GClb (HR 0.33; 95% CI: 0.22, 0.51; p<0.0001). [7] Median PFS was not reached in either arm after a median follow-up duration of 28 months. [7] The overall response rate was 85% in VEN+G arm compared to 71% in GClb arm, p=0.0007. [7] The trial also demonstrated statistically significant improvements in rates of minimal residual disease negativity (less than one CLL cell per 104 leukocytes) in bone marrow and peripheral blood. [7] Overall survival data were not mature at this analysis. [7]
The FDA used the Real-Time Oncology Review and Assessment Aid Pilot Program for this application and granted priority review as well as orphan drug and breakthrough therapy designations. [7] Approval was granted 3.7 months ahead of the Prescription Drug User Fee Act (PDUFA) date. [7]
AbbVie Inc. manufactures Venclexta. [11] It is marketed by both Abbvie and Genentech USA, which is a member of the Roche Group. [11] AbbVie and Genentech are both commercializing the drug within the United States, but only AbbVie has rights to do so outside of the U.S. [17]
According to Reuters 2016 Drugs to Watch, the 2020 forecast sales for venetoclax are US$1.48 billion. [18] : 3, 7–8 Competition as well as potential for combination is expected from other drugs such as ibrutinib and idelalisib, both of which were also approved in 2014 to treat CLL. [18] : 7–8 [19]
As of 2016 [update] , venetoclax had been tested to treat other hematological cancers, including non-Hodgkin's lymphoma, multiple myeloma, diffuse large B-cell lymphoma and follicular lymphoma. [18] : 7–8
On 13 June 2020 at the European Hematology Association (EHA) annual congress, AbbVie and Roche announced the results of a Phase III trial that showed a 34 percent reduction in the risk of death in AML patients who were ineligible for intensive chemotherapy treated with venetoclax plus azacitidine compared to azacitidine plus placebo. [24] [25] [26] Several trials have assessed the combination of venetoclax with intensive chemotherapy in younger AML patients. [27]
Leukemia is a group of blood cancers that usually begin in the bone marrow and result in high numbers of abnormal blood cells. These blood cells are not fully developed and are called blasts or leukemia cells. Symptoms may include bleeding and bruising, bone pain, fatigue, fever, and an increased risk of infections. These symptoms occur due to a lack of normal blood cells. Diagnosis is typically made by blood tests or bone marrow biopsy.
Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes. Early on, there are typically no symptoms. Later, non-painful lymph node swelling, feeling tired, fever, night sweats, or weight loss for no clear reason may occur. Enlargement of the spleen and low red blood cells (anemia) may also occur. It typically worsens gradually over years.
Cytarabine, also known as cytosine arabinoside (ara-C), is a chemotherapy medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and non-Hodgkin's lymphoma. It is given by injection into a vein, under the skin, or into the cerebrospinal fluid. There is a liposomal formulation for which there is tentative evidence of better outcomes in lymphoma involving the meninges.
Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, idiopathic thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis and Epstein–Barr virus-positive mucocutaneous ulcers. It is given by slow intravenous infusion. Biosimilars of Rituxan include Blitzima, Riabni, Ritemvia, Rituenza, Rixathon, Ruxience, and Truxima.
Bruton's tyrosine kinase, also known as tyrosine-protein kinase BTK, is a tyrosine kinase that is encoded by the BTK gene in humans. BTK plays a crucial role in B cell development.
Richter's transformation (RT), also known as Richter's syndrome, is the conversion of chronic lymphocytic leukemia (CLL) or its variant, small lymphocytic lymphoma (SLL), into a new and more aggressively malignant disease. CLL is the circulation of malignant B lymphocytes with or without the infiltration of these cells into lymphatic or other tissues while SLL is the infiltration of these malignant B lymphocytes into lymphatic and/or other tissues with little or no circulation of these cells in the blood. CLL along with its SLL variant are grouped together in the term CLL/SLL.
Bendamustine, sold under the brand name Treanda among others, is a chemotherapy medication used in the treatment of chronic lymphocytic leukemia (CLL), multiple myeloma, and non-Hodgkin's lymphoma. It is given by injection into a vein.
Obinutuzumab, sold under the brand name Gazyva among others, is a humanized anti-CD20 monoclonal antibody used as a treatment for cancer. It was originated by GlycArt Biotechnology AG and developed by Roche.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy. It was initially regarded as a form of lymphocyte-derived cutaneous lymphoma and alternatively named CD4+CD56+ hematodermic tumor, blastic NK cell lymphoma, and agranular CD4+ NK cell leukemia. Later, however, the disease was determined to be a malignancy of plasmacytoid dendritic cells rather than lymphocytes and therefore termed blastic plasmacytoid dendritic cell neoplasm. In 2016, the World Health Organization designated BPDCN to be in its own separate category within the myeloid class of neoplasms. It is estimated that BPDCN constitutes 0.44% of all hematological malignancies.
Phosphoinositide 3-kinase inhibitors are a class of medical drugs that are mainly used to treat advanced cancers. They function by inhibiting one or more of the phosphoinositide 3-kinase (PI3K) enzymes, which are part of the PI3K/AKT/mTOR pathway. This signal pathway regulates cellular functions such as growth and survival. It is strictly regulated in healthy cells, but is always active in many cancer cells, allowing the cancer cells to better survive and multiply. PI3K inhibitors block the PI3K/AKT/mTOR pathway and thus slow down cancer growth. They are examples of a targeted therapy. While PI3K inhibitors are an effective treatment, they can have very severe side effects and are therefore only used if other treatments have failed or are not suitable.
Midostaurin, sold under the brand name Rydapt & Tauritmo both by Novartis, is a multi-targeted protein kinase inhibitor that has been investigated for the treatment of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and advanced systemic mastocytosis. It is a semi-synthetic derivative of staurosporine, an alkaloid from the bacterium Streptomyces staurosporeus.
Ibrutinib, sold under the brand name Imbruvica among others, is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase (BTK). Blocking BTK inhibits the B-cell receptor pathway, which is often aberrantly active in B cell cancers. Ibrutinib is therefore used to treat such cancers, including mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström's macroglobulinemia. Ibrutinib also binds to C-terminal Src Kinases. These are off-target receptors for the BTK inhibitor. Ibrutinib binds to these receptors and inhibits the kinase from promoting cell differentiation and growth. This leads to many different side effects like left atrial enlargement and atrial fibrillation during the treatment of Chronic Lymphocytic Leukemia.
Idelalisib, sold under the brand name Zydelig, is a medication used to treat certain blood cancers.
Vadastuximab talirine is an antibody-drug conjugate (ADC) directed to CD33 (siglec-3) which is a transmembrane receptor expressed on cells of myeloid lineage. The experimental drug, being developed by Seattle Genetics, was in clinical trials for the treatment of acute myeloid leukemia (AML).
R-HDAC, or R-HD-AraC ((R)ituximab plus (H)igh (D)ose (A)ra-(C)) is a chemotherapy regimen that is used, alternating with R-Maxi-CHOP, as part of so-called "Nordic protocol" of treating mantle cell lymphoma. It consists of monoclonal antibody rituximab and high-dose antimetabolite cytarabine.
FCM, or FMC in the context of chemotherapy is an acronym for a chemotherapy regimen that is used in the treatment of indolent B cell non-Hodgkin's lymphomas. In combination with Rituximab, this regimen is called R-FCM or R-FMC, or FCM-R, FMC-R.
Acalabrutinib, sold under the brand name Calquence, is a medication used to treat various types of non-Hodgkin lymphoma, including mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic Lymphoma (CLL/SLL). It may be used both in relapsed as well as in treatment-naive settings.
Duvelisib, sold under the brand name Copiktra, is a medication used to treat chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and follicular lymphoma after other treatments have failed. It is taken by mouth. It is a PI3 kinase inhibitor.
Umbralisib, sold under the brand name Ukoniq, is an anti-cancer medication for the treatment of marginal zone lymphoma (MZL) and follicular lymphoma (FL). It is taken by mouth.
Zanubrutinib, sold under the brand name Brukinsa, is an anticancer medication used for the treatment of mantle cell lymphoma (MCL), Waldenström's macroglobulinemia (WM), marginal zone lymphoma (MZL), and chronic lymphocytic leukemia (CLL). Zanubrutinib is classified as a Bruton's tyrosine kinase (BTK) inhibitor. It is given by mouth.