ABBV AbbVie Inc

NORTH CHICAGO, Ill., June 13, 2020 /PRNewswire/ -- AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, today announced the positive results from the VIALE-A (M15-656) trial, which demonstrated that previously-untreated patients with acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy treated with venetoclax (VENCLEXTA® or VENCLYXTO®) plus azacitidine achieved a 34 percent reduction in the risk of death compared to azacitidine in combination with placebo (Hazard Ratio [HR]=0.66 [95 percent CI 0.52-.85], p=0.001).¹ Patients receiving the venetoclax combination achieved improved median overall survival (OS) (14.7 months versus 9.6 months in the placebo arm), and 66.4 percent of patients treated with venetoclax plus azacitidine had a composite complete remission (CR + CRi) compared to 28.3 percent treated with azacitidine plus placebo.

The data set was presented for the first time as late-breaking data during the virtual 25th European Hematology Association (EHA) Annual Congress (abstract #LB2601).

"Patients living with AML may be too sick to endure chemotherapy, and they face one of the most aggressive types of blood cancer," said Neil Gallagher, M.D., Ph.D., chief medical officer, AbbVie. "The positive results from the VIALE-A study underscore the significant impact venetoclax plus azacitidine can have on improved survival and complete response in a previously-untreated patient population."

The randomized, double-blind, placebo-controlled, Phase 3 VIALE-A trial evaluated the efficacy and safety of venetoclax in combination with azacitidine in patients with AML who are ineligible for standard induction therapy. The study met its primary endpoints of statistically significant improvement of OS and composite complete remission rate (CR + CRi). OS was the sole primary endpoint in the U.S. and U.S. reference countries, and OS and CR + CRi were co-primary endpoints in China, Japan, the European Union (EU) and EU reference countries.

"AML is a challenging blood cancer marked by low survival rates – especially among older patients who are not eligible for intensive induction chemotherapy – which leaves them with few treatment options," said Courtney D. DiNardo, M.D., MSCE, Department of Leukemia, Division of Cancer Medicine at MD Anderson and the lead study investigator. "The VIALE-A results provide further insights in venetoclax to significantly extend overall survival and achieve better response rates than azacitidine alone. Venetoclax in combination with azacitidine is an effective therapeutic approach for previously-untreated AML in patients who cannot withstand chemotherapy."

The study also met secondary endpoints, with the venetoclax combination arm resulting in a CR rate of 36.7 percent, a CR with partial hematologic recovery (CRh) rate of 64.7 percent and a composite complete remission rate (CR + CRi) of 66.4 percent, compared to 17.9 percent CR, 22.8 percent CRh and 28.3 percent CR + CRi in the placebo arm.

The observed safety profile is generally consistent with the known safety profiles of venetoclax combined with azacitidine and the known safety profiles of the two medications alone. The most common (occurring in >10 percent of patients) grade 3/4 adverse events in patients receiving venetoclax plus azacitidine were thrombocytopenia (45 percent), neutropenia (42 percent), febrile neutropenia (42 percent), anemia (26 percent), leukopenia (21 percent), pneumonia (20 percent) and hypokalemia (11 percent).

AML is the most common acute leukemia in the world.² An estimated 160,000 people are currently living with the disease globally with an incidence rate of 103 new cases per 100,000 people.² It is also among the most difficult blood cancers to treat.³ Despite advances in available therapies and care, the five-year survival rate for patients diagnosed with AML remains approximately 28 percent.⁴ AML typically worsens quickly, and due to age and comorbidities, not all patients can tolerate intensive induction chemotherapy.⁵ 

In November 2018, AbbVie received accelerated approval in the U.S. for venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine (LDAC) for the treatment of newly-diagnosed AML in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. Approval was also granted in Mexico, Israel, Puerto Rico, Peru, Brazil, Russia, Argentina, Guatemala, Uruguay, Lebanon, Bahrain, Kazakhstan, Panama, Saudi Arabia, Taiwan, Australia, Qatar, United Arab Emirates and Belarus.

Venetoclax 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 the VIALE-A (M15-656) Phase 3 Trial
A total of 433 treatment-naïve, intensive chemotherapy ineligible AML patients were randomized in the double-blind, placebo-controlled Phase 3 VIALE-A trial. The trial was designed to evaluate the efficacy and safety of venetoclax in combination with azacitidine (n=286) compared with placebo in combination with azacitidine (n=145).⁶ 

About VENCLEXTA®/VENCLYXTO® (venetoclax) 
VENCLEXTA®/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. VENCLEXTA/VENCLYXTO targets the BCL-2 protein and works to help restore the process of apoptosis.

VENCLEXTA/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 and other cancers. VENCLEXTA/VENCLYXTO is approved in more than 50 countries, including the U.S.

Uses and Important VENCLEXTA® (venetoclax) U.S. Safety Information⁷

Uses
VENCLEXTA is a prescription medicine used:

• to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
• in combination with azacitidine, or decitabine, or low-dose cytarabine to treat adults with newly-diagnosed acute myeloid leukemia (AML) who:
• • are 75 years of age or older, or
  • have other medical conditions that prevent the use of standard chemotherapy.

This indication is approved under accelerated approval based on response rates. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials

It is not known if VENCLEXTA is safe and effective in children.

Important Safety Information

What is the most important information I should know about VENCLEXTA?

VENCLEXTA can cause serious side effects, including:

Tumor lysis syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause kidney failure, the need for dialysis treatment, and may lead to death. Your healthcare provider will do tests to check your risk of getting TLS before you start taking VENCLEXTA. You will receive other medicines before starting and during treatment with VENCLEXTA to help reduce your risk of TLS. You may also need to receive intravenous (IV) fluids into your vein. Your healthcare provider will do blood tests to check for TLS when you first start treatment and during treatment with VENCLEXTA. It is important to keep your appointments for blood tests. Tell your healthcare provider right away if you have any symptoms of TLS during treatment with VENCLEXTA, including fever, chills, nausea, vomiting, confusion, shortness of breath, seizures, irregular heartbeat, dark or cloudy urine, unusual tiredness, or muscle or joint pain.

Drink plenty of water during treatment with VENCLEXTA to help reduce your risk of getting TLS. Drink 6 to 8 glasses (about 56 ounces total) of water each day, starting 2 days before your first dose, on the day of your first dose of VENCLEXTA, and each time your dose is increased.

Your healthcare provider may delay, decrease your dose, or stop treatment with VENCLEXTA if you have side effects.

Who should not take VENCLEXTA?

Certain medicines must not be taken when you first start taking VENCLEXTA and while your dose is being slowly increased because of the risk of increased TLS.

• Tell your healthcare provider about all the medicines you take, including prescription and over-the- counter medicines, vitamins, and herbal supplements. VENCLEXTA and other medicines may affect each other causing serious side effects.
• Do not start new medicines during treatment with VENCLEXTA without first talking with your healthcare provider.

Before taking VENCLEXTA, tell your healthcare provider about all of your medical conditions, including if you:

• have kidney or liver problems.
• have problems with your body salts or electrolytes, such as potassium, phosphorus, or calcium.
• have a history of high uric acid levels in your blood or gout.
• are scheduled to receive a vaccine. You should not receive a "live vaccine" before, during, or after treatment with VENCLEXTA, until your healthcare provider tells you it is okay. If you are not sure about the type of immunization or vaccine, ask your healthcare provider. These vaccines may not be safe or may not work as well during treatment with VENCLEXTA.
• are pregnant or plan to become pregnant. VENCLEXTA may harm your unborn baby. If you are able to become pregnant, your healthcare provider should do a pregnancy test before you start treatment with VENCLEXTA, and you should use effective birth control during treatment and for at least 30 days after the last dose of VENCLEXTA. If you become pregnant or think you are pregnant, tell your healthcare provider right away.
• are breastfeeding or plan to breastfeed. It is not known if VENCLEXTA passes into your breast milk. Do not breastfeed during treatment with VENCLEXTA.

What should I avoid while taking VENCLEXTA?

You should not drink grapefruit juice or eat grapefruit, Seville oranges (often used in marmalades), or starfruit while you are taking VENCLEXTA. These products may increase the amount of VENCLEXTA in your blood.

What are the possible side effects of VENCLEXTA?

VENCLEXTA can cause serious side effects, including:

• Low white blood cell counts (neutropenia). Low white blood cell counts are common with VENCLEXTA, but can also be severe. Your healthcare provider will do blood tests to check your blood counts during treatment with VENCLEXTA.
• Infections. Death and serious infections such as pneumonia and blood infection (sepsis) have happened during treatment with VENCLEXTA. Your healthcare provider will closely monitor and treat you right away if you have a fever or any signs of infection during treatment with VENCLEXTA.

Tell your healthcare provider right away if you have a fever or any signs of an infection during treatment with VENCLEXTA.

The most common side effects of VENCLEXTA when used in combination with obinutuzumab or rituximab or alone in people with CLL or SLL include low white blood cell counts; low platelet counts; low red blood cell counts; diarrhea; nausea; upper respiratory tract infection; cough; muscle and joint pain; tiredness; and swelling of your arms, legs, hands, and feet.

The most common side effects of VENCLEXTA in combination with azacitidine or decitabine or low-dose cytarabine in people with AML include low white blood cell counts; nausea; diarrhea; low platelet counts; constipation; fever with low white blood cell counts; low red blood cell counts; infection in blood; rash; dizziness; low blood pressure; fever; swelling of your arms, legs, hands, and feet; vomiting; tiredness; shortness of breath; bleeding; infection in lung; stomach (abdominal) pain; pain in muscles or back; cough; and sore throat.

VENCLEXTA may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if you have concerns about fertility.

These are not all the possible side effects of VENCLEXTA. For more information, ask your healthcare provider or pharmacist.

You are encouraged to report negative side effects of prescription drugs to the FDA.
Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

If you cannot afford your medication, contact www.medicineassistancetool.org for assistance.

The full U.S. prescribing information, including Medication Guide, for VENCLEXTA can be found here. 

Indication and Important VENCLYXTO (venetoclax) EU Safety Information⁸

Indication

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.

Contraindications

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 tumor lysis syndrome (TLS). Concomitant use of preparations containing St. John's wort as VENCLYXTO efficacy may be reduced.

Special Warnings & Precautions for Use

TLS, including fatal events, has occurred in patients with previously treated CLL with high tumour burden when treated with VENCLYXTO. VENCLYXTO poses a risk for TLS in the initial 5-week 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. Patients should be assessed for risk and should receive appropriate prophylaxis, monitoring, and management for TLS.

Neutropenia (grade 3 or 4) has been reported and complete blood counts should be monitored throughout the treatment period. 

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.

Drug Interactions

CYP3A inhibitors may increase VENCLYXTO plasma concentrations. 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, physicians should refer to the SmPC for dose adjustment recommendations. At steady daily dose:  moderate or strong CYP3A inhibitors must be used, physicians should refer to the VENCLYXTO summary of product characteristics (SmPC) for dose adjustment recommendations.

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.

Adverse Reactions

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 and in 15% of patients treated with the combination of venetoclax and 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. 

Specific Populations

Patients with reduced renal function (CrCl <80 mL/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS.  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 full summary of product characteristics (SmPC) at https://www.ema.europa.eu/en/documents/product-information/venclyxto-epar-product-information_en.pdf. Globally, prescribing information varies; refer to the individual country product label for complete information.

About AbbVie in Oncology
At AbbVie, we strive to discover and develop medicines that deliver transformational improvements in cancer treatment by uniquely combining our deep knowledge in core areas of biology with cutting-edge technologies, and by working together with our partners – scientists, clinical experts, industry peers, advocates, and patients. We remain focused on delivering these transformative advances in treatment across some of the most debilitating and widespread cancers. We are also committed to exploring solutions to help patients obtain access to our cancer medicines. AbbVie's oncology portfolio now consists of marketed medicines and a pipeline containing multiple new molecules being evaluated worldwide in more than 300 clinical trials and more than 20 different tumor types. For more information, please visit http://www.abbvie.com/oncology.

About AbbVie
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.

Forward-Looking Statements
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 2019 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.

¹ DiNardo, C.D., Jonas, B.A., et al. A Randomized, Double-Blind, Placebo-Controlled Study of Venetoclax With Azacitidine Vs. Azacitidine In Treatment-Naïve Patients with Acute Myeloid Leukemia Ineligible For Intensive Therapy: The Phase 3 VIALE-A Trial. (2020). https://library.ehaweb.org/eha/2020/eha25th/303390/courtney.dinardo.a.randomized.double-blind.placebo-controlled.study.of.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D2%2Amedia%3D3%2Ace_id%3D1766%2Aces_id%3D27014%2Amarker%3D794%2Afeatured%3D16775
² Puty, T.C., Sarraf, J.S., Do Carmo Almeida, T.C. et al. Evaluation of the impact of single-nucleotide polymorphisms on treatment response, survival and toxicity with cytarabine and anthracyclines in patients with acute myeloid leukaemia: a systematic review protocol. Syst Rev 8, 109 (2019).
³ 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.
⁴ National Cancer Institute (2018). Acute Myeloid Leukemia - SEER Stat Fact Sheets. https://seer.cancer.gov/statfacts/html/amyl.html.
⁵ Pettit, K and Odenike, O. Defining and Treating Older Adults with Acute Myeloid Leukemia Who Are Ineligible for Intensive Therapies. Front Oncol. 2015; 5:250.
⁶ ClinicalTrials.gov (2019). NCT02993523: A Study of Venetoclax in Combination With Azacitidine Versus Azacitidine in Treatment Naïve Subjects With Acute Myeloid Leukemia Who Are Ineligible for Standard Induction Therapy. https://clinicaltrials.gov/ct2/show/NCT02993523.
⁷ VENCLEXTA (venetoclax) [Package Insert]. North Chicago, IL.: AbbVie Inc.
⁸ Summary of Product Characteristics for VENCLYXTO (venetoclax). Ludwigshafen, Germany: AbbVie Deutschland GmbH & Co. KG.

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