AbbVie Announces U.S. FDA Approval of VENCLEXTA® (venetoclax tablets) in Combination with Rituximab as a Fixed Duration Treatment for Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Patients Who Have Received One Prior Therapy

NORTH CHICAGO, Ill., June 8, 2018 /PRNewswire/ -- AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, today announced the U.S. Food and Drug Administration (FDA) has approved, under priority review, VENCLEXTA® (venetoclax tablets) in combination with rituximab for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy.¹

The approval is based on MURANO Phase 3 clinical trial data which demonstrated a significant improvement in progression-free survival (PFS) for relapsed/refractory (R/R) CLL patients, reducing the risk of disease progression or death by 81 percent when compared to bendamustine in combination with rituximab, a standard of care chemoimmunotherapy regimen.¹

Clinical trial patients who received VENCLEXTA plus rituximab also achieved an overall response rate (ORR) of 92 percent and those who received the chemoimmunotherapy regimen achieved an ORR of 72 percent.¹  

The safety profile of the combination is consistent with the known safety profile of VENCLEXTA. The most common adverse reactions (ARs), greater than or equal to 20 percent, with VENCLEXTA in combination with rituximab were neutropenia, diarrhea, upper respiratory tract infection, fatigue, cough and nausea.¹

VENCLEXTA plus rituximab is the first oral-based, chemotherapy-free combination in CLL that allows patients an option for fixed treatment duration. 

"VENCLEXTA now gives indicated patients a new opportunity to significantly reduce the risk of their disease progressing, compared to a current standard of care. This combination provides previously treated CLL or SLL patients with a chemotherapy-free, fixed duration treatment allowing patients the ability to stop treatment after approximately two years," said Michael Severino, M.D., executive vice president, research and development, and chief scientific officer, AbbVie. "This is an important step for patients and we look forward to continuing to provide new treatment options for people living with difficult-to-treat blood cancers." 

VENCLEXTA has been granted four Breakthrough Therapy Designations (BTDs) from the FDA including for the combination treatment regimen of VENCLEXTA plus rituximab for patients with R/R CLL.² The approval of the VENCLEXTA plus rituximab treatment regimen marks the second approval granted under priority review by the FDA for VENCLEXTA. Outside of the U.S., regulatory submissions to and reviews with health authorities are underway.

"The approval of the combination of VENCLEXTA plus rituximab for patients with relapsed/refractory CLL or SLL validates the results seen in the Phase 3 trial, including the significant improvement in progression-free survival over a standard of care comparator arm," said Prof. John Seymour, MBBS, Ph.D., lead investigator of the MURANO study and Director of Cancer Medicine at the Peter MacCallum Cancer Centre & Royal Melbourne Hospital in Australia. "Progression-free survival is considered a gold standard for demonstrating clinical benefit in oncology."

CLL is typically a slow-progressing cancer of the bone marrow and blood in which types of 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  SLL is closely related to CLL. However, unlike CLL, SLL cancer cells are typically found in the lymph nodes and spleen rather than the bone marrow and the blood. In the U.S., approximately 5,000 cases of SLL are diagnosed annually.⁴

The FDA has also approved expansion of the indication of VENCLEXTA as monotherapy for CLL or SLL patients, with or without 17p deletion, who have received one prior therapy. Previously, VENCLEXTA, the first B-cell lymphoma-2 (BCL-2) inhibitor in CLL, was approved under accelerated approval in the U.S. in April 2016 as a monotherapy 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.⁵ 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.

About the MURANO Study

A total of 389 patients with 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 22-85).¹ 

Efficacy in the U.S. was based on PFS 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 ORR, complete response [CR] plus complete response with incomplete marrow recovery [CRi], nodular partial response [nPR], or partial response [PR]) and overall survival (OS).¹ 

The most common 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, discontinuations 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 discontinuations 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 last rituximab 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).¹

About the Monotherapy Studies

M13-982 (NCT01889186) was a multicenter, open-label, single-arm clinical trial of 106 patients with CLL with 17p deletion who had received at least one prior therapy. The efficacy of VENCLEXTA was evaluated by ORR as assessed by an IRC using the International Workshop for Chronic Lymphocytic Leukemia (iwCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines (2008). The median time on treatment at the time of evaluation was 12.1 months (range: 0 to 21.5 months). Results showed the ORR was 80 percent (95% CI: 71, 87). The CR and CRi rates were 6 percent and 2 percent, respectively; and the nPR and PR rates were 3 percent and 70 percent. Time to first response (TTFR), duration of response (DOR), and MRD-negativity were also evaluated.¹

M12-175 (NCT01328626) was a multicenter, open-label study that enrolled previously treated patients with CLL or SLL, including those with 17p deletion. Efficacy was evaluated in 67 patients (59 with CLL, 8 with SLL) according to 2008 iwCLL guidelines. The median duration of treatment at the time of evaluation was 22.1 months (range: 0.5 to 50.1 months). As assessed by an IRC, ORR was 71 percent (95% CI: 58, 82), CR+CRi rate was 7 percent, and PR rate was 64 percent. Based on investigator assessments, the ORR in patients with CLL was 80 percent (14 percent CR+CRi, 66 percent PR+nPR). For the 8 patients with SLL, the investigator assessed ORR was 100 percent.¹

M14-032 (NCT02141282) was a multicenter, open-label study that evaluated the efficacy of VENCLEXTA in patients with CLL who had been previously treated with and progressed on or after ibrutinib or idelalisib. Efficacy was evaluated in 127 patients (91 with prior ibrutinib, 36 with prior idelalisib) according to 2008 iwCLL guidelines. At the time of analysis, the median duration of treatment was 14.3 months (range: 0.1 to 31.4 months). Based on IRC assessment, the ORR was 70 percent (95% CI: 61, 78), with a CR+CRi rate of 1 percent, and a PR rate of 69 percent. Based on investigator assessment, the ORR was 65 percent (95% CI: 56, 74).¹

Safety was evaluated in a pooled dataset of 352 patients from the three monotherapy studies. Fatal ARs were reported in 2 percent of patients, most commonly (2 patients) from septic shock. Serious ARs were reported in 52 percent of patients, with the most frequent (≥5 percent) being pneumonia (9 percent), febrile neutropenia (5 percent), and sepsis (5 percent). Discontinuations due to ARs occurred in 9 percent of patients, and dose reductions due to ARs occurred in 13 percent of patients. The most common ARs (≥20 percent) any grade were neutropenia (50 percent), diarrhea (43 percent), nausea (42 percent), upper respiratory tract infection (36 percent), anemia (33 percent), fatigue (32 percent), thrombocytopenia (29 percent), musculoskeletal pain (29 percent), edema (22 percent), and cough (22 percent). The most common Grade 3 or 4 ARs (≥5 percent) were neutropenia (45 percent), thrombocytopenia (20 percent), anemia (18 percent), pneumonia (8 percent), lymphopenia (7 percent), and febrile neutropenia (6 percent).¹

About VENCLEXTA® (venetoclax tablets) (US)

VENCLEXTA is an oral BCL-2 inhibitor that targets a specific protein in the body called BCL-2.¹ When you have CLL or SLL, BCL-2 may build up and prevent cancer cells from self-destructing naturally. VENCLEXTA targets BCL-2 in order to help restore the process of apoptosis.¹

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 with venetoclax, which is currently being evaluated in clinical trials in several hematologic cancers.^{6, 7, 8, 9} 

VENCLEXTA (VENCLYXTO® in the EU) is currently approved as a monotherapy in 53 nations, including the U.S. AbbVie, in collaboration with Roche and Genentech, is currently working with regulatory agencies around the world to bring this medicine to additional eligible patients in need.

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.⁵ The FDA approved this indication under accelerated approval based on overall response rate.⁵ With this approval, VENCLEXTA is now approved 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. ¹   

VENCLEXTA has been granted four Breakthrough Therapy Designations from the FDA including for the combination treatment regimen of VENCLEXTA plus rituximab for patients with CLL who have received at least one prior therapy.² This designation is intended to expedite the development and review of therapies for serious or life-threatening conditions.¹⁰ The approval of the VENCLEXTA plus rituximab treatment regimen marks the second approval granted under priority review by the FDA for VENCLEXTA. In January 2016, AbbVie announced that the FDA granted priority review for the NDA application for single agent VENCLEXTA.

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.

The most common side effects of VENCLEXTA when used in combination with rituximab include diarrhea, nausea, upper respiratory tract infection and feeling tired.

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://abbvieoncology.com.

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

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