AbbVie Receives US FDA Accelerated Approval for VENCLEXTA® (venetoclax) for Treatment of Newly-Diagnosed Acute Myeloid Leukemia Patients Ineligible for Intensive Chemotherapy

NORTH CHICAGO, Ill., Nov. 21, 2018 /PRNewswire/ -- AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval to VENCLEXTA^® (venetoclax tablets) in combination with azacitidine, or decitabine, or low-dose cytarabine (LDAC) 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. 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.⁷

Intensive chemotherapy may not be appropriate for all patients diagnosed with AML.⁸ An analysis of 446 older (≥70 years of age) AML patients concluded that intensive chemotherapy can be delivered but may not be beneficial to most.⁸ There are a number of factors why AML patients may be unable to tolerate intensive chemotherapy, such as age, performance status and comorbidities.⁸  Median survival in patients not eligible for intensive chemotherapy is five to 10 months.¹

"AML is an extremely aggressive and debilitating blood cancer, and outcomes for patients ineligible for intensive chemotherapy are very poor," said Michael Severino, M.D., executive vice president of research and development and chief scientific officer, AbbVie. "This new approval for VENCLEXTA marks a significant milestone for AbbVie and, more importantly, for patients diagnosed with this deadly disease. We look forward to continuing our work developing VENCLEXTA and advancing treatment options in other aggressive cancers."

The FDA accelerated approval is based on two open-label non-randomized trials in patients with newly-diagnosed AML who were age 75 years or older, or had comorbidities that precluded the use of intensive induction chemotherapy: M14-358, a trial evaluating VENCLEXTA in combination with azacitidine (n=67) or decitabine (n=13), and M14-387, a trial of VENCLEXTA and LDAC (n=61).⁷ Efficacy was established based on the rate of complete remission (CR) and duration of CR.⁷

The M14-358 trial showed that VENCLEXTA in combination with azacitidine resulted in a CR rate of 37 percent and a CR with partial hematologic recovery (CRh) rate of 24 percent. The median follow-up of patients included in the study was 7.9 months (range: 0.4 to 36 months). At the time of analysis, for patients who achieved a CR, the median observed time in remission was 5.5 months (range: 0.4 to 30 months), with patients achieving a first CR or CRh at a median of 1 month (range: 0.7 to 8.9 months). For patients taking VENCLEXTA in combination with decitabine, the CR rate was 54 percent and the CRh rate was 7.7 percent. The median follow-up of patients taking this combination was 11 months (range: 0.7 to 21 months). At the time of analysis, for patients who achieved a CR, the median observed time in remission was 4.7 months (range: 1 to 18 months), with patients achieving a first CR or CRh at a median of 1.9 months (range: 0.8 to 4.2 months).⁷

The M14-387 trial showed that patients receiving VENCLEXTA in combination with LDAC achieved a CR rate of 21 percent and a CRh rate of 21 percent. The median follow-up of patients was 6.5 months (range: 0.3 to 34 months). At the time of analysis, for patients who achieved a CR, the median observed time in remission was six months (range: 0.03 to 25 months), with patients achieving a first CR or CRh at a median of 1 month (range: 0.8 to 9.4 months).⁷

For patients taking VENCLEXTA in combination with azacitidine, serious ARs were reported in 75 percent of patients. The most frequent serious adverse reactions (ARs; ≥5 percent) were febrile neutropenia, pneumonia (excluding fungal), sepsis (excluding fungal), respiratory failure and multiple organ dysfunction syndrome. For those taking VENCLEXTA and decitabine, serious ARs were reported in 85 percent of patients. The most frequent serious ARs (≥5 percent) were febrile neutropenia, sepsis (excluding fungal), pneumonia (excluding fungal), diarrhea, fatigue, cellulitis and localized infection.⁷

For patients taking VENCLEXTA in combination with LDAC, serious ARs were reported in 95 percent of patients. The most frequent serious adverse reactions (ARs; ≥5 percent) were febrile neutropenia, sepsis (excluding fungal), hemorrhage, pneumonia (excluding fungal) and device-related infection.⁷

The challenges of treating AML, including in older adults who are more likely to be ineligible for intensive chemotherapy, are an ongoing topic of discussion among the medical community. Dr. Daniel Pollyea, clinical director of leukemia services at University of Colorado Hospital reflected on his experience treating patients with AML here: "A Physicians View: Facing the Challenges of Treating AML in Older Adults." 

"Many of my patients are ineligible for the intensive treatment for AML, which typically involves intensive chemotherapy. Only a minority of AML patients older than 60 are able to tolerate the standard chemotherapy required to achieve optimal results," said Dr. Pollyea. "Having a new medicine to treat AML is encouraging for my patients and their families. VENCLEXTA's approval is a true breakthrough for AML patients ineligible for intensive chemotherapy."

VENCLEXTA, an oral B-cell lymphoma-2 (BCL-2) inhibitor, has been granted four Breakthrough Therapy Designations (BTDs) from the FDA.^3,4,5,6 The FDA approved VENCLEXTA in combination with azacitidine, or decitabine, or low-dose cytarabine 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. 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.⁷ 

The approval of VENCLEXTA in AML marks the third approval granted under priority review by the FDA for VENCLEXTA.⁷ VENCLEXTA is being studied in two ongoing Phase 3 studies in the AML patient population ineligible for intensive chemotherapy.^9,10

Venetoclax is being studied in several other hematologic malignancies including chronic lymphocytic leukemia (CLL), multiple myeloma (MM), non-Hodgkin lymphoma (NHL) and myelodysplastic syndrome (MDS).^11,12,13 Venetoclax is being developed by AbbVie and Roche and 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 Clinical Trials that Supported Accelerated Approval in AML

The FDA accelerated approval is based on two open-label non-randomized trials in patients with newly-diagnosed AML who were age 75 years or older, or had comorbidities that precluded the use of intensive induction chemotherapy based on at least one of the following criteria: baseline Eastern Cooperative Oncology Group (ECOG) performance status of 2-3, severe cardiac or pulmonary comorbidity, moderate hepatic impairment, or CLcr <45 mL/min or other comorbidity. Efficacy was established based on the rate of complete remission (CR) and duration of CR.⁷

Study M14-358 was a non-randomized, open-label clinical trial of VENCLEXTA in combination with azacitidine (N=84) or decitabine (N=31) in patients with newly-diagnosed AML. Of those patients, 67 who received azacitidine combination and 13 who received decitabine combination were age 75 or older or had comorbidities that precluded the use of intensive induction chemotherapy. Patients received VENCLEXTA via a daily ramp-up to a final 400 mg once daily dose.⁷ 

Azacitidine (N=67):
The CR rate was 37 percent (95% confidence interval [CI]: 26, 50), and the CRh rate was 24 percent (95% CI: 14, 36). The median follow-up was 7.9 months (range: 0.4 to 36 months) for VENCLEXTA in combination with azacitidine. At the time of analysis, for patients who achieved a CR, the median observed time in remission was 5.5 months (range: 0.4 to 30 months). The observed time in remission is the time from the start of CR to the time of data cut-off date or relapse from CR. Median time to first CR or CRh was 1.0 month (range: 0.7 to 8.9 months).⁷

Of patients treated with VENCLEXTA in combination with azacitidine, 7.5 percent (5/67) subsequently received stem cell transplant.⁷ 

The study enrolled 17 additional patients who did not have known comorbidities that preclude the use of intensive induction chemotherapy. For those patients, the CR rate was 35 percent (95% CI: 14, 62) and the CRh rate was 41 percent (95% CI: 18, 67). Seven patients subsequently received stem cell transplant.⁷

The most common ARs (≥30 percent) of any grade were nausea, diarrhea, constipation, neutropenia, thrombocytopenia, hemorrhage, peripheral edema, vomiting, fatigue, febrile neutropenia, rash and anemia.⁷ Serious ARs were reported in 75 percent of patients.⁷ The most frequent serious adverse reactions (ARs; ≥5 percent) were febrile neutropenia, pneumonia (excluding fungal), sepsis (excluding fungal), respiratory failure and multiple organ dysfunction syndrome.⁷

Decitabine (N=13):
The CR rate was 54 percent (95% CI: 25, 81), and the CRh rate was 7.7 percent (95% CI: 0.2, 36). The median follow-up was 11 months (range: 0.7 to 21 months) for VENCLEXTA in combination with decitabine. At the time of analysis, for patients who achieved a CR, the median observed time in remission was 4.7 months (range: 1.0 to 18 months). The observed time in remission is the time from the start of CR to the time of data cut-off date or relapse from CR. Median time to first CR or CRh was 1.9 months (range: 0.8 to 4.2 months).⁷

The study enrolled 18 additional patients who did not have known comorbidities that preclude the use of intensive induction chemotherapy. For those patients, the CR rate was 56 percent (95% CI: 31, 79) and the CRh rate was 22 percent (95% CI: 6.4, 48). Three patients subsequently received stem cell transplant.⁷

The most common ARs (≥30 percent) of any grade were febrile neutropenia, constipation, fatigue, thrombocytopenia, abdominal pain, dizziness, hemorrhage, nausea, pneumonia (excluding fungal), sepsis (excluding fungal), cough, diarrhea, neutropenia, back pain, hypotension, myalgia, oropharyngeal pain, peripheral edema, pyrexia and rash. Serious ARs were reported in 85 percent of patients.⁷ The most frequent serious ARs (≥5 percent) were febrile neutropenia, sepsis (excluding fungal), pneumonia (excluding fungal), diarrhea, fatigue, cellulitis and localized infection.⁷

Low-dose cytarabine (N=61):
Study M14-387 was a non-randomized, open-label clinical trial of VENCLEXTA in combination with low dose cytarabine (N=82) in patients with newly-diagnosed AML, including patients with previous exposure to a hypomethylating agent for an antecedent hematologic disorder. Of those patients, 61 were age 75 or older or had comorbidities that precluded the use of intensive induction chemotherapy. Patients initiated VENCLEXTA via daily ramp-up to a final 600 mg once-daily dose.⁷ 

The CR rate was 21 percent (95% CI: 12, 34), and the CRh rate was 21 percent (95% CI: 12, 34). The median follow-up was 6.5 months (range: 0.3 to 34 months). At the time of analysis, for patients who achieved a CR, the median observed time in remission was 6.0 months (range: 0.03 to 25 months). The observed time in remission is the time from the start of CR to the time of data cut-off date or relapse from CR. Median time to first CR or CRh was 1.0 month (range: 0.8 to 9.4 months).⁷

The study enrolled 21 additional patients who did not have known comorbidities that preclude the use of intensive induction chemotherapy. For those patients, the CR rate was 33 percent (95% CI:15, 57) and the CRh rate was 24 percent (95% CI: 8.2, 47). One patient subsequently received stem cell transplant.⁷

The most common ARs (≥30 percent) of any grade were nausea, thrombocytopenia, hemorrhage, febrile neutropenia, neutropenia, diarrhea, fatigue, constipation and dyspnea. Serious ARs were reported in 95 percent of patients. The most frequent serious adverse reactions (ARs; ≥5 percent) were febrile neutropenia, sepsis (excluding fungal), hemorrhage, pneumonia (excluding fungal) and device-related infection.⁷

About VENCLEXTA^® (venetoclax) (US)

VENCLEXTA^® 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 targets the BCL-2 protein and works to help restore the process of apoptosis.⁷ 

VENCLEXTA 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. 

In April 2016, the U.S. FDA first granted accelerated approval of VENCLEXTA for the treatment of patients with CLL with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy.¹⁴ The FDA approved this indication under accelerated approval based on overall response rate.¹⁴ Based on the results of the MURANO study, VENCLEXTA was approved in June 2018 for the treatment of patients with CLL or SLL, with or without 17p deletion, who have received at least one prior therapy in combination with rituximab or as monotherapy.⁷ 

Venetoclax is approved in more than 50 countries, including the U.S. AbbVie, in collaboration with Roche, is currently working with regulatory agencies around the world to bring this medicine to additional eligible patients in need.

Use and Important Safety Information (US)

What is VENCLEXTA^® (venetoclax)?

VENCLEXTA is a prescription medicine used:

• to treat adults with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least 1 prior treatment.
• 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.

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 when taking 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 tumor lysis syndrome (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 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 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, 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. 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 rituximab in people with CLL include low white blood cell counts, diarrhea, upper respiratory tract infection, cough, tiredness, and nausea.

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

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 http://www.fda.gov/medwatch or call 1-800-FDA-1088.

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

The full U.S. prescribing information, including Medication Guide, for VENCLEXTA can be found here. 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. With the acquisitions of Pharmacyclics in 2015 and Stemcentrx in 2016, our research and development efforts, and through collaborations, AbbVie's oncology portfolio now consists of marketed medicines and a pipeline containing multiple new molecules being evaluated worldwide in more than 200 clinical trials and more than 20 different tumor types. For more information, please visit http://www.abbvie.com/oncology.

About AbbVie

AbbVie is a global, research and development-based biopharmaceutical company committed to developing innovative advanced therapies for some of the world's most complex and critical conditions. The company's mission is to use its expertise, dedicated people and unique approach to innovation to markedly improve treatments across four primary therapeutic areas: immunology, oncology, virology and neuroscience. In more than 75 countries, AbbVie employees are working every day to advance health solutions for people around the world. For more information about AbbVie, please visit us at www.abbvie.com. Follow @abbvie on Twitter, Facebook, LinkedIn or Instagram.

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, challenges to intellectual property, competition from other products, 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 2017 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.

References

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³ Farrell A. Grant-Breakthrough Therapy Designation (CLL). Department of Health and Human Services. 2015:1-3.
⁴ Farrell A. Grant-Breakthrough Therapy Designation (CLL). Department of Health and Human Services. 2015:1-3.
⁵ Farrell A. Grant-Breakthrough Therapy Designation (AML). Department of Health and Human Services. 2016:1-3.
⁶ Farrell A. Grant-Breakthrough Therapy Designation (AML). Department of Health and Human Services. 2017:1-3.
⁷ VENCLEXTA (venetoclax) [Package Insert]. North Chicago, Ill.: AbbVie Inc.
⁸ Kantarjian H, et al. Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood. 2010;116(22):4422-4429.
⁹ Clinicaltrials.gov (2018). NCT02993523: A study of venetoclax in combination with azacytidine versus azacytidine in treatment naïve subjects with acute myeloid leukemia who are ineligible for standard induction therapy. Accessed November 2018.
¹⁰ Clinicaltrials.gov (2018). NCT03069352: A study of venetoclax in combination with low dose cytarabine versus low dose cytarabine alone in treatment naïve patients with acute myeloid leukemia who are ineligible for intensive chemotherapy. Accessed November 2018.
¹¹ Clinicaltrials.gov (2018). NCT01794520: Study evaluating ABT-199 in subjects with relapsed or refractory Multiple Myeloma. Accessed November 2018.
¹² Clinicaltrials.gov (2018). NCT01328626: A Phase 1 study evaluating the safety and pharmacokinetics of ABT-199 in subjects with relapsed or refractory Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma. Accessed November 2018.
¹³ Clinicaltrials.gov (2018). NCT02942290: A study evaluating venetoclax in combination with azacytidine in subjects with treatment-naïve higher-risk myelodysplastic syndromes (MDS). Accessed November 2018.
¹⁴ U.S. Food and Drug Administration (2016). News and Events: FDA approves new drug for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm495253.htm. Accessed November 2018.

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