AbbVie Receives FDA Accelerated Approval of Venclexta™ (venetoclax) Tablets, the First BCL-2 Inhibitor in Relapsed/Refractory Chronic Lymphocytic Leukemia Patients with 17p Deletion

NORTH CHICAGO, Ill., April 11, 2016 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced the U.S. Food and Drug Administration (FDA) has granted accelerated approval of Venclexta™ (venetoclax) tablets for patients diagnosed with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA-approved test, who have received at least one prior therapy.¹ The FDA approved this indication under accelerated approval based on overall response rate, and continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial. The FDA approved Venclexta as a first-in-class, oral, once-daily medicine¹ that selectively inhibits the BCL-2 protein.¹ The BCL-2 protein blocks apoptosis (programmed cell death) of cells, including some cancer cells, and can be overexpressed in CLL cells.¹ Venclexta is being developed by AbbVie and Genentech, a member of the Roche Group. It is marketed collaboratively by the companies in the U.S. and by AbbVie outside of the U.S.

"The FDA's approval of Venclexta marks a major milestone for our company, and more importantly for the patients diagnosed with relapsed/refractory CLL who harbor the 17p deletion," said Richard Gonzalez, chairman of the board and chief executive officer of AbbVie. "BCL-2 inhibition is a novel mechanism which brings a new treatment option to patients who need additional therapies."

AbbVie expects Venclexta, a tablet taken orally, will become commercially available in the U.S. within a week.

"Results from the clinical trial program show that Venclexta provides significant overall response among previously treated patients with CLL with 17p deletion," said Matthew S. Davids, M.D., M.MSc., a physician at the Dana-Farber Cancer Institute, Assistant Professor of Medicine at Harvard Medical School, and a leading principal clinical investigator in the Venclexta clinical trial program. "Based on the efficacy and safety profile observed in the clinical trials, Venclexta can be an important and unique addition in the fight against relapsed/refractory CLL in patients with 17p deletion."

"The approval of Venclexta as a first-in-class BCL-2 inhibitor gives physicians an important option for the treatment of relapsed/refractory CLL harboring the 17p deletion," said Michael Severino, M.D., executive vice president of research and development and chief scientific officer, AbbVie. "With the efficacy observed in this patient population, Venclexta has the potential to be an important and new therapy, advancing our efforts to bring novel treatment options to patients with this type of cancer."

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 United States, CLL accounts for more than 14,000 newly diagnosed cases of leukemia each year.³ The 17p deletion is found in 3 to 10 percent of previously untreated cases and up to 30 to 50 percent of relapsed or refractory cases.⁴ The deletion is a genomic alteration in which a part of chromosome 17 is absent.^3,4 Patients with this mutation typically have a poor prognosis and a life expectancy of less than two to three years.^4,5

In January 2016, AbbVie announced that the FDA granted priority review for the NDA application of venetoclax as a single agent.⁶ The FDA also granted venetoclax three Breakthrough Therapy designations – the first for venetoclax for the treatment of chronic lymphocytic leukemia (CLL) in previously treated (relapsed/refractory) patients with the 17p deletion genetic mutation,⁷ the second for venetoclax in combination with rituximab for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL),⁸ and the third for patients with untreated (treatment-naïve) acute myeloid leukemia (AML) who are ineligible to receive standard induction therapy (high-dose chemotherapy).⁹ According to the FDA, Breakthrough Therapy designation is intended to expedite the development and review of therapies for serious or life-threatening conditions.¹⁰ Additionally, in January 2016, AbbVie announced that the European Medicines Agency (EMA) had validated its Marketing Authorization Application (MAA) for venetoclax for the treatment of patients with CLL with 17p deletion or TP53 mutation.¹¹

Venclexta Clinical Trial Program
The safety and efficacy of Venclexta was evaluated in an open-label, multicenter clinical trial of 106 previously-treated CLL patients with 17p deletion. In the study, patients with 17p deletion were identified using Vysis CLL FISH Probe Kit, which is FDA-approved for selection of patients for Venclexta treatment. Patients received Venclexta via a weekly ramp-up schedule starting at 20 mg and ramping to 50 mg, 100 mg, 200 mg and finally 400 mg once daily. Patients continued to receive 400 mg of Venclexta once daily until disease progression or unacceptable toxicity. The median time on treatment at the time of evaluation was 12.1 months (range: 0 to 21.5 months). The primary efficacy endpoint, overall response rate (ORR), was 80 percent. The median time to first response was 0.8 months (range: 0.1 to 8.1 months). Median duration of response (DOR) has not been reached with approximately 12 months of median follow-up. The DOR ranged from 2.9 to 19.0+ months.¹

The safety of single agent Venclexta is based on pooled data of 240 patients with previously treated CLL from two Phase 2 trials and one Phase 1 trial. The most common adverse reactions (≥20%) were neutropenia (low white blood cell count), diarrhea, nausea, low red blood cell count, upper respiratory tract infection, thrombocytopenia (low platelet count) and fatigue. Serious adverse reactions were reported in 43.8 percent of patients. The most frequent serious adverse reactions (≥2%) were pneumonia, low white blood cell count with fever (febrile neutropenia), fever, abnormal breakdown of red blood cells resulting in low red blood cell count (autoimmune hemolytic anemia (AIHA)), low red blood cell count, and tumor lysis syndrome (TLS). Discontinuations due to adverse reactions occurred in 8.3 percent of patients. The most frequent adverse reactions leading to drug discontinuation were thrombocytopenia and AIHA. Dosage adjustments due to adverse reactions occurred in 9.6 percent of patients. The most frequent adverse reactions leading to dose adjustments were neutropenia, febrile neutropenia, and thrombocytopenia. Tumor lysis syndrome (TLS) is an important, identified risk when initiating Venclexta. TLS is caused by the fast breakdown of cancer cells. In 66 CLL patients starting with a daily dose of 20 mg and increasing over five weeks to a daily dose of 400 mg, the rate of TLS was 6 percent.  No TLS with clinical consequences such as acute renal failure, cardiac arrhythmias or sudden death and/or seizures were observed in these patients.¹

The full prescribing information for Venclexta can be found here.

Patient Assistance Program
For those who qualify, AbbVie and Genentech plan to offer patient assistance programs for people taking Venclexta.

About Venclexta
Venclexta is an oral B-cell lymphoma-2 (BCL-2) inhibitor indicated for the treatment of patients with relapsed/refractory CLL with 17p deletion, as detected by an FDA-approved test.¹ The BCL-2 protein prevents apoptosis (programmed cell death) of some cells, including lymphocytes, and can be overexpressed in CLL cells.¹ Venclexta is designed to selectively inhibit the BCL-2 protein.¹ Venclexta was developed in collaboration with Genentech and Roche. Together, the companies are committed to BCL-2 research with Venclexta, which is currently being evaluated in Phase 3 clinical trials for the treatment of relapsed/refractory CLL, along with early phase studies in several cancers.

Use
VENCLEXTA™ (venetoclax) is a prescription medicine used to treat people with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least one prior treatment.

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 doctor will do tests for TLS. It is important to keep your appointments for blood tests. 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. Tell your doctor 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.

• Tell your doctor 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 doctor.

What should I tell my doctor before taking VENCLEXTA?
Before taking VENCLEXTA, tell your doctor 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 doctor tells you it is okay.
• Are pregnant or plan to become pregnant. VENCLEXTA may harm your unborn baby. If you are able to become pregnant, your doctor 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.
• 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 count (neutropenia). Low white blood cell counts are common with VENCLEXTA, but can also be severe. Your doctor will do blood tests to check your blood counts during treatment with VENCLEXTA. Tell your doctor right away if you have a fever or any signs of an infection.

The most common side effects of VENCLEXTA include diarrhea, nausea, low red blood cell count, upper respiratory tract infection, low platelet count, and feeling tired.

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

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

About AbbVie in Oncology
AbbVie's oncology research is focused on the discovery and development of targeted therapies that work against the processes cancers need to survive. By investing in new technologies and approaches, AbbVie is breaking ground in some of the most widespread and difficult-to-treat cancers, including glioblastoma multiforme, multiple myeloma and chronic lymphocytic leukemia. AbbVie's oncology pipeline includes multiple new molecules in clinical trials being studied in more than 15 different cancers and tumor types. For more information on AbbVie in oncology, please visit http://oncology.abbvie.com.

About AbbVie
AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott Laboratories. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. Together with its wholly owned subsidiary, Pharmacyclics, AbbVie employs more than 28,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.

AbbVie Forward-Looking Statements
Some statements in this news release may be 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," in AbbVie's 2014 Annual Report on Form 10-K and in item 1A, "Risk Factors" of Part II of AbbVie's second quarter 2015 Quarterly Report on Form 10-Q, which have 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 Venclexta [Package Insert]. North Chicago, Ill.: AbbVie Inc.
² Sellner L. et al. What do we do with chronic lymphocytic leukemia with 17p deletion? Curr Hematol Malig Rep. 2013;8(1):81-90.
³ American Cancer Society (2015). Leukemia – Chronic Lymphocyctic. http://www.cancer.org/acs/groups/cid/documents/webcontent/003111-pdf.pdf. Accessed January 18, 2016.
⁴ Schnaiter A. et al. 17p deletion in chronic lymphocytic leukemia: risk stratification and therapeutic approach. Hematol Oncol Clin N Am. 2013;27:289–301.
⁵ Stilgenbauer S. et al. Understanding and managing ultra high-risk chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2010(1):481-488.
⁶ Farrell A. Filing Communication (Priority). Department of Health and Human Services. 2015: 1-5.
⁷ Farrell A. Grant-Breakthrough Therapy Designation (17p del CLL). Department of Health and Human Services. 2015: 1-3. 
⁸ Farrell A. Grant–Breakthrough Therapy Designation (CLL). Department of Health and Human Services. 2016: 1-3.
⁹ Farrell A. Grant–Breakthrough Therapy Designation (AML). Department of Health and Human Services. 2016: 1-3.
¹⁰ U.S. Food and Drug Administration (2015). Frequently Asked Questions: Breakthrough Therapies. http://www.fda.gov/regulatoryinformation/legislation/significantamendmentstothefdcact/fdasia/ucm341027.htm. Accessed March 15, 2016.
¹¹ Kozarewicz P. EMEA/H/C/004106/000. European Medicines Agency. 2015: 1-2.

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