Minimal Residual Disease Negativity Data, a Measure of Undetectable Disease, Added to VENCLEXTA® (venetoclax tablets) Label

- Minimal residual disease (MRD)-negativity is defined as having disease at a threshold of less than one chronic lymphocytic leukemia (CLL) cell per 10,000 lymphocytes in the blood or bone marrow[1]

- In the Phase 3 MURANO study, 53 percent of previously-treated CLL patients treated with the combination of VENCLEXTA and rituximab achieved MRD-negativity (undetectable disease) in their blood after approximately nine months, while 12 percent of patients treated with the standard chemoimmunotherapy regimen of bendamustine plus rituximab achieved MRD-negativity[2]

- Label expansion follows the recent FDA approval of VENCLEXTA in combination with rituximab as the first chemotherapy-free combination with a fixed treatment duration for previously-treated CLL that allows patients to stop treatment after approximately two years[2]

- Milestone marks the second label expansion for VENCLEXTA in 2018

News provided by

AbbVie

Sep 11, 2018, 08:17 ET

NORTH CHICAGO, Ill., Sept. 11, 2018 /PRNewswire/ -- AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, today announced the U.S. Food and Drug Administration (FDA) has expanded the label for VENCLEXTA^® (venetoclax tablets) in combination with rituximab to include information about patients with previously-treated chronic lymphocytic leukemia (CLL) who achieved minimal residual disease (MRD)-negativity in the Phase 3 MURANO trial.

MRD-negativity occurs when less than one CLL cell per 10,000 lymphocytes can be detected in the blood or bone marrow using sensitive analytical methods.¹ More than half (53 percent [103/194]) of patients treated with the VENCLEXTA and rituximab combination achieved MRD-negativity (undetectable disease) after approximately nine months on therapy (three months after the last dose of rituximab), while 12 percent (23/195) of patients treated with the standard chemoimmunotherapy regimen of bendamustine plus rituximab achieved MRD-negativity.²

"With this label expansion for VENCLEXTA, physicians now have additional information on MRD-negativity, which is becoming an increasingly important goal when caring for their previously-treated CLL patients," said Michael Severino, M.D., executive vice president, research and development, and chief scientific officer, AbbVie. "VENCLEXTA plus rituximab is the first chemotherapy-free combination for previously-treated CLL that allows patients the ability to stop treatment after approximately two years. This label expansion is another important milestone in our efforts to advance care for patients with difficult-to-treat blood cancers."

In the MURANO study, the MRD-negativity rate was evaluated in patients who responded to treatment. The rate of MRD-negativity in patients with a complete response or complete response with incomplete marrow recovery (CR/CRi) at nine months on therapy (three months after the last dose of rituximab) was 3 percent (6/194) in the VENCLEXTA plus rituximab arm and 2 percent (3/195) in the bendamustine plus rituximab arm.²

CLL is typically a slow-growing cancer of the bone marrow and blood in which white blood cells called lymphocytes become cancerous and multiply abnormally.³ In the U.S., CLL accounts for more than 20,000 newly diagnosed cases of leukemia each year.³

"CLL is a chronic, life-altering cancer marked by periods of remission and relapse, making it an emotional rollercoaster for patients. Many patients who enter remission worry that the disease will relapse," said Prof. John Seymour, MBBS, Ph.D., lead investigator of the MURANO study and director of clinical haematology at the Peter MacCallum Cancer Centre & Royal Melbourne Hospital in Australia. "The rates of MRD-negativity seen with VENCLEXTA plus rituximab are very encouraging. A goal in treating patients with CLL is to help them achieve the longest remission possible. MRD-negativity provides us with yet another potential tool for evaluating the effectiveness of new therapies."

VENCLEXTA, a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein, has been granted four Breakthrough Therapy Designations (BTDs) from the FDA.⁴In June 2018, the FDA approved, under priority review, VENCLEXTA in combination with rituximab for the treatment of patients with CLL or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy.² The addition of MRD-negativity data in these previously-treated CLL patients represents the second label expansion for VENCLEXTA in 2018.

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. ^5,6,7,8

About the MURANO Study and MRD Results

A total of 389 patients with relapsed or refractory (R/R) CLL who had received at least one prior therapy were enrolled in the international, multicenter, open-label, randomized (1:1) MURANO study (NCT02005471). The study was designed to evaluate the efficacy and safety of VENCLEXTA in combination with rituximab (194 patients) compared with bendamustine in combination with rituximab (195 patients). The median age of patients in the trial was 65 years (range: 22 to 85 years).²

Efficacy in the U.S. was based on progression-free survival (PFS; the time people live without their disease worsening) as assessed by an Independent Review Committee (IRC). Median PFS with VENCLEXTA in combination with rituximab was not reached compared with 18.1 months for bendamustine in combination with rituximab (hazard ratio: 0.19; 95% confidence interval [CI]: 0.13, 0.28; P<0.0001). The median follow-up for PFS was 23.4 months (range: 0 to 37.4+ months). Additional efficacy endpoints included IRC-assessed response rate (defined as overall response rate [ORR], complete response [CR] plus complete response with incomplete marrow recovery [CRi], nodular partial response [nPR], or partial response [PR]), overall survival (OS) and MRD-negativity).²

MRD was evaluated in patients who achieved a PR or better using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The definition of negative status was less than one CLL cell per 10,000 lymphocytes. After nine months on therapy (three months after the last dose of rituximab), the MRD-negativity rate in peripheral blood was 53 percent (103/194) in the VENCLEXTA plus rituximab arm and 12 percent (23/195) in the bendamustine plus rituximab arm.² The MRD-negativity rate in patients with a CR/CRi at this time point was 3 percent (6/194) in the VENCLEXTA plus rituximab arm and 2 percent (3/195) in the bendamustine plus rituximab arm.

The most common adverse reactions (ARs; ≥20 percent) of any grade for VENCLEXTA in combination with rituximab were neutropenia (65 percent), diarrhea (40 percent), upper respiratory tract infection (39 percent), fatigue (22 percent), cough (22 percent) and nausea (21 percent). In the VENCLEXTA plus rituximab arm, discontinuation due to any ARs occurred in 16 percent of patients, dose reduction in 15 percent, and dose interruption in 71 percent. In the bendamustine plus rituximab arm, ARs led to treatment discontinuation in 10 percent of patients, dose reduction in 15 percent, and dose interruption in 40 percent. In the VENCLEXTA in combination with rituximab arm, neutropenia led to dose interruption of VENCLEXTA in 46 percent of patients and discontinuation in 3 percent, and thrombocytopenia led to discontinuation in 3 percent of patients. In the VENCLEXTA in combination with rituximab arm, fatal ARs that occurred in the absence of disease progression and within 30 days of the last VENCLEXTA treatment and/or 90 days of the last rituximab treatment were reported in 2 percent (4/194) of patients. Serious ARs were reported in 46 percent of patients, with the most frequent (≥5 percent) being pneumonia (9 percent).²

About VENCLEXTA^® (venetoclax tablets) (U.S.)

VENCLEXTA^® is a first-in-class medicine that selectively binds and inhibits the B-cell lymphoma-2 (BCL-2) protein. In some blood cancers and other cancerous tumors, BCL-2 builds up and prevents cancer cells from undergoing their natural death or self-destruction process, which is called apoptosis. VENCLEXTA targets the BCL-2 protein and works to restore the process of apoptosis.²

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.⁹ The FDA approved this indication under accelerated approval based on overall response rate.⁹ Based on the results of the MURANO study, VENCLEXTA was granted full approval 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.²

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.

For more information, visit www.abbvie.com.

What is VENCLEXTA^® (venetoclax tablets)?
VENCLEXTA is a prescription medicine used to treat people with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with or without 17p deletion, who have received at least one prior treatment.

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

Important VENCLEXTA^® (venetoclax tablets) US 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 health care provider will do tests to check your risk of getting TLS 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 health care provider will do blood tests in your first 5 weeks of treatment to check you for TLS during treatment with VENCLEXTA. It is important to keep your appointments for blood tests. Tell your health care 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.

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.

Tell your health care 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 health care provider.

Before taking VENCLEXTA, tell your health care 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 health care provider tells you it is okay. If you are not sure about the type of immunization or vaccine, ask your health care 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 health care 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 health care 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 count (neutropenia). Low white blood cell counts are common with VENCLEXTA, but can also be severe. Your health care provider will do blood tests to check your blood counts during treatment with VENCLEXTA. Tell your health care provider right away if you have a fever or any signs of an infection while taking VENCLEXTA.

The most common side effects of VENCLEXTA when used in combination with rituximab include low white blood cell count, diarrhea, upper respiratory tract infection, cough, tiredness, and nausea.

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

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

These are not all the possible side effects of VENCLEXTA. Tell your health care provider if you have any side effect that bothers you or that does not go away.

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

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.

Patient Assistance
For those who qualify, patient assistance options are available for people taking VENCLEXTA in the U.S. If people cannot afford their medication, they should contact www.pparx.org for assistance.

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 or 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, 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

¹ Hallek M, et al. Guidelines for diagnosis, indications for treatment, response assessment and supportive management of chronic lymphocytic leukemia. Blood. 2018;131(25):2745-2760.
² VENCLEXTA (venetoclax tablets) [Package Insert]. North Chicago, Ill.: AbbVie Inc.
³ American Cancer Society (2018). Chronic Lymphocytic Leukemia (CLL). https://www.cancer.org/content/dam/CRC/PDF/Public/8679.00.pdf. Accessed August 2018.
⁴ Farrell A. Grant-Breakthrough Therapy Designation (CLL). Department of Health and Human Services. 2016:1-3.
⁵ Clinicaltrials.gov (2018). NCT01994837: A Phase 2 Study of ABT-199 in subjects with Acute Myelogenous Leukemia (AML). Accessed August 2018.
⁶ Clinicaltrials.gov (2018). NCT01794520: Study evaluating ABT-199 in subjects with relapsed or refractory Multiple Myeloma. Accessed August 2018.
⁷ 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 August 2018.
⁸Clinicaltrials.gov (2018). NCT01889186: A study of the efficacy of ABT-199 in subjects with relapsed/refractory or previously untreated chronic lymphocytic leukemia with the 17p deletion. Accessed August 2018.
⁹ 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 August 2018.