AbbVie Receives European Commission Approval of VENCLYXTO® (venetoclax) in Combination with a Hypomethylating Agent for Patients with Newly Diagnosed Acute Myeloid Leukemia Who Are Ineligible for Intensive Chemotherapy
- VENCLYXTO® (venetoclax) in combination with a hypomethylating agent is a new regimen approved by the European Commission (EC) for patients with newly diagnosed acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy 
- Approval is based on data from AbbVie's clinical trial program for VENCLYXTO, including the Phase 3 VIALE-A trial, which showed patients treated with VENCLYXTO in combination with azacitidine demonstrated improvements in overall survival versus patients treated with placebo in combination with azacitidine 
- Approval is also based on results of the Phase 1b M14-358 trial which showed patients treated with VENCLYXTO in combination with azacitidine or decitabine achieved high remission rates 
NORTH CHICAGO, Ill., May 25, 2021 /PRNewswire/ -- AbbVie (NYSE: ABBV) announced today that the European Commission (EC) has approved VENCLYXTO® (venetoclax) in combination with a hypomethylating agent, azacitidine or decitabine, for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy.1 The approval is valid in all 27 member states of the EU, as well as Iceland, Liechtenstein, and Norway.
"VENCLYXTO has proven incremental overall survival in treating newly diagnosed AML in patients who are ineligible for intensive chemotherapy when treated with VENCLYXTO plus azacitidine compared to those treated with azacitidine alone," said Mohamed Zaki, M.D., Ph.D., vice president and head, global oncology development, AbbVie. "We look forward to bringing VENCLYXTO to more AML patients who can potentially benefit from this important new treatment option in EU countries."
This is the third extension of indications for VENCLYXTO, a first-in-class B-cell lymphoma-2 (BCL-2) inhibitor. BCL-2 is a protein that prevents cancer cells from undergoing apoptosis, the process that leads to the natural death or self-destruction of cancer cells.1
This most recent approval is based on results from the Phase 3 double-blind, placebo-controlled VIALE-A (M15-656) and the Phase 1b open-label, nonrandomized, multicenter M14-358 clinical trials. The VIALE-A trial demonstrated patients who received VENCLYXTO in combination with azacitidine showed statistically significantly greater median overall survival (OS) than patients receiving azacitidine alone (p<0.001).2 The Phase 1b M14-358 trial evaluating venetoclax in combination with hypomethylating agents, azacitidine or decitabine, exhibited an overall safety profile that was generally consistent with the known safety profiles of venetoclax combined with azacitidine and the two medications alone.3
In the VIALE-A trial, the most frequently reported serious adverse events (AEs) in the VENCLYXTO plus azacitidine arm and placebo plus azacitidine arm were febrile neutropenia, pneumonia, sepsis, and haemorrhage.2 In the M14-358 trial, the most frequently reported serious AEs in patients receiving VENCLYXTO in combination with decitabine were febrile neutropenia, pneumonia, bacteraemia and sepsis.3
"The European Commission approval of venetoclax combination therapy offers a new option for people facing what is often a devastating acute myeloid leukemia diagnosis," said Zack Pemberton-Whiteley, Chair of the Acute Leukemia Advocates Network. "This approval represents an important advancement for the treatment of AML and offers an option for those who are ineligible for intensive chemotherapy."
In April 2021, AbbVie announced that the European Committee for Medicinal Products for Human Use (CHMP) granted a positive opinion for the Marketing Authorization Application for VENCLYXTO in combination with hypomethylating agents for the treatment of patients with newly diagnosed AML who are ineligible for intensive chemotherapy.
VENCLYXTO is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S.
About Acute Myeloid Leukemia
AML is the most common acute leukemia in the world.4 An estimated 160,000 people are currently living with the disease globally.4 The rate of new cases of acute myeloid leukemia is 4.3 per 100,000 men and women per year.5 It is also among the most difficult blood cancers to treat.6 Despite advances in available therapies and care, the five-year survival rate for patients diagnosed with AML remains approximately 29 percent.5 AML typically worsens quickly, and due to age and comorbidities, not all patients can tolerate intensive chemotherapy.7
About the VENCLYXTO AML Clinical Trial Program
AbbVie's clinical trial program to evaluate VENCLYXTO combination with a hypomethylating agent in patients with newly diagnosed acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy included two studies conducted around the world.
VIALE-A (M15-656) Phase 3 Trial2
The randomized, double-blind, placebo-controlled VIALE-A (M15-656) trial evaluated the efficacy and safety of VENCLYXTO in combination with azacitidine in patients with newly diagnosed AML who were ineligible for intensive chemotherapy. The study met its primary endpoints of statistically significant improvement of overall survival (OS) and composite complete remission (complete remission [CR]+complete remission with incomplete hematologic recovery [CRi]) (CR + CRi). Overall survival was 14.7 months for the VENCLYXTO plus azacitidine arm versus 9.6 months in the placebo plus azacitidine arm, and the composite complete remission rate was 66.4 percent versus 28.3 percent, respectively. The study also met secondary endpoints, with the VENCLYXTO plus azacitidine arm resulting in a CR rate of 36.7 percent vs. 17.9 percent in the placebo plus azacitidine arm. The safety profile of VENCLYXTO plus azacitidine was consistent with the known side-effect profiles of both agents, and adverse events (AEs) were consistent with expectations for an older AML population. The most frequently reported serious AEs in the VENCLYXTO plus azacitidine arm and placebo plus azacitidine arm were febrile neutropenia (in 30 percent and 10 percent), pneumonia (in 17 percent and 22 percent), sepsis (in 6 percent and 8 percent), and haemorrhage (in 9 percent and 6 percent), respectively.2
M14-358 Phase 1b Trial3
The non-randomized, open-label M14-358 trial evaluated VENCLYXTO in combination with azacitidine or decitabine in patients with newly diagnosed AML who were ineligible for intensive chemotherapy. Patients treated with VENCLYXTO in combination with decitabine achieved a CR+CRi rate of 74 percent and a 30-day mortality rate of 6.5 percent. The median follow-up was 40.4 months (range: 0.7 to 42.7 months) for venetoclax in combination with decitabine. The most frequently reported serious AEs (≥5%) in patients receiving VENCLYXTO in combination with decitabine were febrile neutropenia, pneumonia, bacteraemia and sepsis, with neutropenia reported in 35 percent (all grades) and 35 percent (grade 3 or 4) of patients in the venetoclax + decitabine arm. No events of laboratory or clinical TLS were reported with venetoclax in combination with decitabine.
About VENCLYXTO® (venetoclax)
VENCLYXTO® (venetoclax) is a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers, BCL-2 prevents cancer cells from undergoing their natural death or self-destruction process, called apoptosis. VENCLYXTO targets the BCL-2 protein and works to help restore the process of apoptosis.
VENCLYXTO is also approved in combination with obinutuzumab for the treatment of adult patients with previously untreated chronic lymphocytic leukemia (CLL), in combination with rituximab for the treatment of adult patients with CLL who have received at least one prior therapy, and as a monotherapy for the treatment of CLL in the presence or absence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor.1
VENCLYXTO is being developed by AbbVie and Roche. It is jointly commercialized by AbbVie and Genentech, a member of the Roche Group, in the U.S. and by AbbVie outside of the U.S. Together, the companies are committed to BCL-2 research and to studying venetoclax in clinical trials across several blood. Venetoclax is approved in more than 80 countries, including the U.S.
Indications and Important Venclyxto (venetoclax) EU Safety Information1
Venclyxto in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL).
Venclyxto in combination with rituximab is indicated for the treatment of adult patients with CLL who have received at least one prior therapy.
Venclyxto monotherapy is indicated for the treatment of CLL:
- In the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B-cell receptor pathway inhibitor, or
- In the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.
Venclyxto in combination with a hypomethylating agent is indicated for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy.
Hypersensitivity to the active substance or to any of the excipients is contraindicated. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase due to increased risk for tumour lysis syndrome (TLS). Concomitant use of preparations containing St. John's wort as Venclyxto efficacy may be reduced.
Special Warnings & Precautions for Use
Tumour Lysis syndrome, including fatal events, has occurred in patients when treated with Venclyxto. For CLL and AML, please refer to the indication-specific recommendations for prevention of TLS in the Venclyxto summary of product characteristic (SmPC).
Patients should be assessed for risk and should receive appropriate prophylaxis, monitoring, and management for TLS. The risk of TLS is a continuum based on multiple factors, including comorbidities. Venclyxto poses a risk for TLS at initiation and during the dose-titration phase. Changes in electrolytes consistent with TLS that require prompt management can occur as early as 6 to 8 hours following the first dose of Venclyxto and at each dose increase.
Neutropenia (grade 3 or 4) has been reported. Complete blood counts should be monitored throughout the treatment period.
In patients with AML, neutropenia (grade 3 or 4) is common before starting treatment. The neutrophil counts can worsen with Venetoclax in combination with a hypomethylating agent. Neutropenia can recur with subsequent cycles of therapy. Dose modification and interruptions for cytopenias are dependent on remission status.
For CLL and AML, please refer to the indication-specific recommendations for dose modifications for toxicities in the Venclyxto SmPC.
Serious infections including sepsis with fatal outcome have been reported. Monitoring of any signs and symptoms of infection is required. Suspected infections should receive prompt treatment including antimicrobials and dose interruption or reduction as appropriate.
Live vaccines should not be administered during treatment or thereafter until B-cell recovery.
In CLL and AML CYP3A inhibitors may increase Venclyxto plasma concentrations.
In CLL, at initiation and dose-titration phase, strong CYP3A inhibitors are contraindicated due to increased risk for TLS and moderate CYP3A inhibitors should be avoided. If moderate CYP3A inhibitors must be used, please refer to the recommendations for dose modifications in the Venclyxto SmPC.
In AML, please refer to the AML-specific recommendation for dose modifications for potential interactions with CYP3A inhibitors, in the Venclyxto SmPC.
Avoid concomitant use of P-gp and BCRP inhibitors at initiation and during the dose titration phase.
CYP3A4 inducers may decrease Venclyxto plasma concentrations. Avoid coadministration with strong or moderate CYP3A inducers. These agents may decrease venetoclax plasma concentrations.
Co-administration of bile acid sequestrants with VENCLYXTO is not recommended as this may reduce the absorption of VENCLYXTO.
The most commonly occurring adverse reactions (>=20%) of any grade in patients receiving venetoclax in the combination studies with obinutuzumab or rituximab were neutropenia, diarrhoea, and upper respiratory tract infection. In the monotherapy studies, the most common adverse reactions were neutropenia/neutrophil count decreased, diarrhoea, nausea, anaemia, fatigue, and upper respiratory tract infection.
The most frequently occurring serious adverse reactions (>=2%) in patients receiving venetoclax in combination with obinutuzumab or rituximab were pneumonia, sepsis, febrile neutropenia, and TLS. In the monotherapy studies, the most frequently reported serious adverse reactions (>=2%) were pneumonia and febrile neutropenia.
Discontinuations due to adverse reactions occurred in 16% of patients treated with venetoclax in combination with obinutuzumab or rituximab in the CLL14 and Murano studies, respectively. In the monotherapy studies with venetoclax, 11% of patients discontinued due to adverse reactions.
Dosage reductions due to adverse reactions occurred in 21% of patients treated with the combination of venetoclax and obinutuzumab in CLL14, in 15% of patients treated with the combination of venetoclax and rituximab in Murano, and in 14% of patients treated with venetoclax in the monotherapy studies. The most common adverse reaction that led to dose interruptions was neutropenia.
The most commonly occurring adverse reactions (>=20%) of any grade in patients receiving venetoclax in combination with azacitidine or decitabine in the VIALE-A and M14-358, respectively, were thrombocytopenia, neutropenia, febrile neutropenia, nausea, diarrhoea, vomiting, anaemia, fatigue, pneumonia, hypokalaemia, and decreased appetite, haemorrhage, dizziness/syncope, hypotension, headache, abdominal pain, and anaemia.
The most frequently reported serious adverse reactions (≥5%) in patients receiving venetoclax in combination with azacitidine were febrile neutropenia, pneumonia, sepsis and haemorrhage. In M14-358, the most frequently reported serious adverse reactions (≥5%) were febrile neutropenia, pneumonia, bacteraemia and sepsis.
Discontinuations due to adverse reactions occurred in 24% of patients treated with venetoclax in combination with azacitidine in the VIALE-A study, and 26% of patients treated with venetoclax in combination with decitabine in the M14-358 study, respectively.
Dosage reductions due to adverse reactions occurred in 2% of patients in VIALE-A, and in 6 % of patients in M14-358. Venetoclax dose interruptions due to adverse reactions occurred in 72% and 65 % of patients, respectively. The most common adverse reaction that led to dose interruption (>10%) of Venetoclax in VIALE-A, were febrile neutropenia, neutropenia, pneumonia, and thrombocytopenia. The most common adverse reactions that led to dose interruption (≥5%) of venetoclax in M14-358 were febrile neutropenia, neutropenia/neutrophil count decreased, pneumonia, platelet count decreased, and white blood cell count decreased.
Patients with reduced renal function (CrCl <80 mL/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS at initiation and during the dose-titration phase. Safety in patients with severe renal impairment (CrCl <30 mL/min) or on dialysis has not been established, and a recommended dose for these patients has not been determined.
For patients with severe (Child-Pugh C) hepatic impairment, a dose reduction of at least 50% throughout treatment is recommended.
Venclyxto may cause embryo-fetal harm when administered to a pregnant woman. Advise nursing women to discontinue breastfeeding during treatment.
This is not a complete summary of all safety information. See Venclyxto (venetoclax) SmPC at www.ema.europa.eu. Globally, prescribing information varies; refer to the individual country product label for complete information.
About AbbVie in Oncology
At AbbVie, we are committed to transforming standards of care for multiple blood cancers while advancing a dynamic pipeline of investigational therapies across a range of cancer types. Our dedicated and experienced team joins forces with innovative partners to accelerate the delivery of potentially breakthrough medicines. We are evaluating more than 20 investigational medicines in over 300 clinical trials across some of the world's most widespread and debilitating cancers. As we work to have a remarkable impact on people's lives, we are committed to exploring solutions to help patients obtain access to our cancer medicines. For more information, please visit http://www.abbvie.com/oncology.
AbbVie's mission is to discover and deliver innovative medicines that solve serious health issues today and address the medical challenges of tomorrow. We strive to have a remarkable impact on people's lives across several key therapeutic areas: immunology, oncology, neuroscience, eye care, virology, women's health and gastroenterology, in addition to products and services across its Allergan Aesthetics portfolio. For more information about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on Twitter, Facebook, Instagram, YouTube and LinkedIn.
Some statements in this news release are, or may be considered, forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, competition from other products, challenges to intellectual property, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry. Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," of AbbVie's 2020 Annual Report on Form 10-K, which has been filed with the Securities and Exchange Commission. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.
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American Cancer Society (2018). Typical Treatment of Most Types of Acute Myeloid Leukemia (Except Acute Promyelocytic M3). https://www.cancer.org/cancer/acute-myeloid-leukemia/treating/typical-treatment-of-aml.html. Accessed May 20, 2021
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