European Commission Grants Conditional Marketing Approval for AbbVie's VENCLYXTO™ (venetoclax) Monotherapy for Appropriate Patients with Difficult-To-Treat Chronic Lymphocytic Leukaemia

- VENCLYXTO™ (venetoclax) monotherapy is indicated for the treatment of chronic lymphocytic leukaemia (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 inhibitor¹

- VENCLYXTO monotherapy is also indicated for the treatment of CLL in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor¹

- In a Phase 2 clinical trial of VENCLYXTO in 107 patients with previously treated CLL with 17p deletion, overall response rate (ORR) was 79 percent¹

- In a second Phase 2 clinical trial of VENCLYXTO in 64 patients with CLL who had been previously treated with and failed ibrutinib or idelalisib, combined ORR was 64 percent¹

- VENCLYXTO is the first approved BCL-2 inhibitor in Europe

NORTH CHICAGO, Illinois, Dec. 8, 2016 /PRNewswire/ -- AbbVie (NYSE: ABBV), a global biopharmaceutical company, today announced the European Commission (EC) has granted conditional marketing authorization for VENCLYXTO™ (venetoclax) monotherapy for the treatment of chronic lymphocytic leukaemia (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; and for the treatment of CLL in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.¹ The EC approved VENCLYXTO as a first-in-class, oral, once-daily medicine that selectively inhibits the function of the BCL-2 protein.¹ BCL-2 prevents the natural death of cells, including CLL cells.¹ VENCLYXTO is being developed by AbbVie and Genentech, a member of the Roche Group. It is jointly commercialized by the companies in the U.S. and by AbbVie outside of the U.S.

"The European approval of VENCLYXTO is an important step forward for patients with chronic lymphocytic leukaemia in Europe," said Richard Gonzalez, chairman of the board and chief executive officer of AbbVie. "AbbVie has led the way in researching ways to block BCL-2 activity, and, as the first approved BCL-2 inhibitor in Europe, VENCLYXTO delivers on AbbVie's promise to develop cancer medicines where an unmet need exists."

CLL, a cancer of the bone marrow and blood, is typically a slow-progressing cancer.² The 17p deletion, a genomic alteration in which a part of chromosome 17 is absent, is found in 3 to 10 percent of previously untreated CLL cases and up to 30 to 50 percent of relapsed or refractory CLL cases.³ A TP53 mutation occurs in 8 to 15 percent of patients at first-line treatment and up to 35 to 50 percent of cases in refractory CLL.³ Those with the 17p deletion or TP53 mutations often have a particularly poor prognosis³ and a median life expectancy of less than two to three years with current standard-of-care regimens.⁴

Conditional marketing authorization is granted to medicines that address an unmet medical need, where the benefit of its immediate availability to patients outweighs the risk of limited data availability, and where comprehensive data will be provided.⁵

"Results from the clinical trial program show that VENCLYXTO provides significant overall response among both patients with previously treated CLL with 17p deletion and patients with CLL who had been previously treated with and failed a B-cell receptor inhibitor," said Stephan Stilgenbauer, M.D., Ulm University, Germany, investigator in the VENCLYXTO clinical trial program. "While advances in treatment over the past few years have been meaningful for patients in Europe living with CLL, new options are still needed."

"The approval of VENCLYXTO represents an innovation in treatment options for people living with CLL who may harbor the 17p deletion or TP53 mutation and typically have a poor prognosis," said Michael Severino, M.D., executive vice president of research and development and chief scientific officer, AbbVie. "With this approval, we are pleased to be able to bring a new treatment option to patients in more countries around the world with this difficult-to-treat cancer."

In October 2016, AbbVie announced the European Committee for Medicinal Products for Human Use (CHMP) granted a positive opinion for the conditional marketing authorization of VENCLYXTO.⁶ Additionally, the European Medicines Agency (EMA) granted Orphan Drug Designation to VENCLYXTO for the treatment of multiple myeloma,⁷ a type of cancer that forms in plasma cells in bone marrow,⁸ and for diffuse large B-cell lymphoma (DLBCL),⁹ an aggressive type of lymphoma and the most common form of non-Hodgkin lymphoma (NHL).¹⁰ Previously, the EMA granted Orphan Drug Designation to VENCLYXTO for the treatment of CLL⁶ and for the treatment of acute myeloid leukaemia (AML),¹¹ the most common type of acute leukaemia in adults.¹² Orphan Drug Designation is granted to therapies aimed at the treatment, prevention or diagnosis of life-threatening diseases that affect no more than five in 10,000 persons in the EU and for which no satisfactory therapy is available. The medicine must also provide significant benefit to those affected by the condition.¹³

VENCLYXTO Clinical Trial Program
Study 1: Previously treated patients with CLL harboring 17p deletion
The safety and efficacy of VENCLYXTO was evaluated in a Phase 2, single arm, open-label, multi-center study in 107 patients (main cohort) with previously treated CLL with 17p deletion, with an additional 51 patients in a safety expansion cohort. Patients followed a 4- to 5-week dose-titration schedule starting at 20 mg and increasing to 50 mg, 100 mg, 200 mg and finally 400 mg once-daily. Patients continued to receive VENCLYXTO 400 mg once daily until disease progression or unacceptable toxicity was observed. The median time on treatment at the time of evaluation was 12 months (range: 0 to 22 months) for the main cohort. The median time on treatment for the combined cohort (main cohort plus safety expansion cohort, N=158) was 25 months (range: 0.5 to 50 months). The main cohort was assessed by an independent review committee, while the combined cohort was assessed by the investigators. Results showed:¹

• The primary efficacy endpoint, overall response rate (ORR), was 79 percent (95% Confidence Interval [CI]: 70.5, 86.6) in the main cohort and 77 percent (95% CI: 69.9, 83.5) in the combined cohort.
• Median duration of response (DOR) was not reached in the main cohort and was 27.5 months (95% CI: 26.5, NR) for the combined cohort.
• Median progression-free survival (PFS) was not reached in the main cohort and was 27.2 months (95% CI: 21.9, NR) for the combined cohort.
• Complete remission (CR) plus complete remission with incomplete marrow recovery (CRi) was achieved in 7 percent of patients in the main cohort and 18 percent of patients in the combined cohort.
• Partial remission (PR) was reached in 69 percent of patients in the main cohort and 53 percent of patients in the combined cohort.
• Nodular partial remission (nPR) was reached in 3 percent of patients in the main cohort and 6 percent of patients in the combined cohort.
• Minimal residual disease (MRD) was evaluated in 93 of 158 patients who achieved CR, CRi or nPR with VENCLYXTO. MRD negativity in peripheral blood was achieved in 27 percent (41/158) of patients, including 15 patients who were MRD negative in the bone marrow. MRD negativity is an exploratory endpoint.

Study 2: Patients with CLL who have failed a B-cell receptor inhibitor
The safety and efficacy of VENCLYXTO was evaluated in a Phase 2 open-label, multi-center, non-randomized study in patients with CLL who had been previously treated with and failed ibrutinib (median number of prior oncology treatments was 4 [range: 1 to 12]) or idelalisib (median number of prior oncology treatments was 3 [range: 1 to 11]) therapy. Patients received VENCLYXTO via a recommended dose-titration schedule. Patients continued to receive VENCLYXTO 400 mg once daily until disease progression or unacceptable toxicity was observed. At the time of data cut-off, 64 patients were enrolled and treated with VENCLYXTO. Of these, 43 patients had received prior ibrutinib therapy (Arm A) and 21 had received prior idelalisib therapy (Arm B). Of the patients, 91 percent (39/42) in Arm A and 67 percent (14/21) in Arm B had relapsed on or were refractory to ibrutinib and idelalisib, respectively. Chromosomal aberrations were 11q deletion (30%, 19/62), 17p deletion (36%, 23/61), TP53 mutation (26%, 16/61) and unmutated IgVH (86%, 36/42). At the time of evaluation, median duration of treatment with VENCLYXTO was 11.7 months (range: 0.1 to 17.9 months). Results showed:¹

• The primary efficacy endpoint, ORR, was 67 percent (95% CI: 51.5, 80.9) in Arm A, 57 percent (95% CI: 34, 78.2) in Arm B and 64 percent (95% CI: 51.1, 75.7) in the total study population based on investigator assessment. The efficacy data were further evaluated by an IRC demonstrating a combined ORR of 67 percent (Arm A: 70 percent, Arm B: 62 percent).
• The ORR for patients with 17p deletion/TP53 mutation was 71 percent (15/21) (95% CI: 47.8, 88.7) in Arm A and 50 percent (1/2) (95% CI: 1.3, 98.7) in Arm B.
• For patients without 17p deletion/TP53 mutation, the ORR was 68 percent (15/22) (95% CI: 45.1, 86.1) in Arm A and 63 percent (12/19) (95% CI: 38.4, 83.7) in Arm B.
• Median PFS and DOR were not reached with median follow-up of approximately 12 months for Arm A and 9 months for Arm B.
• CR plus CRi was achieved in 7 percent of patients in Arm A, 14 percent of patients in Arm B and 9 percent of patients in the total patient population, per investigator assessment.
• PR was reached in 56 percent of patients in Arm A, 43 percent of patients in Arm B and 52 percent of patients in the total patient population, per investigator assessment.
• nPR was reached in 5 percent of patients in Arm A, zero percent in Arm B and 3 percent in the total patient population, per investigator assessment.

The safety of VENCLYXTO is based on pooled data of 296 patients treated in two Phase 2 studies and one Phase 1 study. In all, the studies enrolled patients with previously treated CLL, including 188 patients with 17p deletion and 92 patients who had failed a B-cell receptor inhibitor. The most commonly occurring adverse reactions (≥20 percent) of any grade in patients receiving VENCLYXTO were neutropenia/neutrophil count decreased, diarrhoea, nausea, anemia, upper respiratory tract infection, fatigue, hyperphosphatemia, vomiting and constipation. The most frequently reported serious adverse reactions (≥2 percent) were pneumonia, febrile neutropenia and tumour lysis syndrome (TLS). Discontinuations due to adverse reactions occurred in 9.1 percent of patients. Dosage adjustments due to adverse reactions occurred in 11.8 percent of patients.¹

About VENCLYXTO™ (venetoclax)
VENCLYXTO™ (venetoclax), an oral B-cell lymphoma-2 (BCL-2) inhibitor, is indicated for the treatment of chronic lymphocytic leukaemia (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; and for the treatment of CLL in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B-cell receptor pathway inhibitor.¹ It is also being evaluated for the treatment of patients with various blood cancer types.^{1,14,15,16,17} The BCL-2 protein prevents apoptosis (programmed cell death) of some cells, including lymphocytes, and can be overexpressed in CLL cells.¹ VENCLYXTO, which is given once-daily, is designed to selectively inhibit the function of the BCL-2 protein.¹

VENCLYXTO is being developed by AbbVie and Genentech, a member of the Roche Group. It is jointly commercialized by the companies 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 Phase 3 clinical trials for the treatment of relapsed/refractory CLL, along with studies in several other cancers.

In April 2016, the U.S. Food and Drug Administration (FDA) granted accelerated approval of VENCLEXTA™ (venetoclax) tablets 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.¹⁸ 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.¹⁸ Venetoclax is also currently approved in Argentina, Puerto Rico and Canada. AbbVie, in collaboration with Roche and Genentech, is currently working with regulatory agencies around the world to bring this medicine to eligible patients in need.

Important EU Safety Information

Contraindications
Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase due to increased risk for tumour lysis syndrome (TLS). Concomitant use of preparations containing St. John's wort as VENCLYXTO efficacy may be reduced. Hypersensitivity to the active substance or to any of the excipients is contraindicated.

Special Warnings & Precautions for Use
Tumour lysis syndrome (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 ramp-up phase. Changes in blood chemistries 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 for TLS. Blood chemistries should be monitored and abnormalities managed promptly. More intensive measures (including hospitalization) should be employed as overall risk increases.

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

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 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: If moderate or strong CYP3A inhibitors must be used, physicians should refer to the 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.

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 were neutropenia/neutrophil count decreased, diarrhoea, nausea, anemia, upper respiratory tract infection, fatigue, hyperphosphatemia, vomiting and constipation.

The most frequently occurring adverse reactions (>=2%) were pneumonia, febrile neutropenia and TLS. 

Discontinuations due to adverse reactions occurred in 9.1% of patients and dosage adjustments due to adverse reactions occurred in 11.8% of patients.

Specific Populations 
VENCLYXTO may cause embryo-fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid pregnancy during treatment. 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 www.ema.europa.eu. Globally, prescribing information varies; refer to the individual country product label for complete information.

About AbbVie in Oncology
AbbVie is striving to outsmart cancer by working with scientists, physicians, industry peers, patient advocacy groups and most importantly patients, to discover, develop and provide new therapies that will have a remarkable impact on the lives of people around the world affected by cancer. Our goal is to provide medicines that make a transformational improvement in cancer treatment and outcomes for cancer patients. By exploring and investing in new pathways, technologies and approaches, AbbVie is breaking ground in some of the most widespread and difficult-to-treat cancers. We are also exploring solutions to help patients obtain access to our cancer medicines. With the acquisition of Pharmacyclics in 2015 and Stemcentrx in 2016, and through several collaborations, AbbVie's oncology portfolio consists of marketed medicines and a pipeline containing multiple new molecules being evaluated worldwide in nearly 200 clinical trials in 20 different tumor types. For more information about AbbVie Oncology, please visit http://abbvieoncology.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 our Facebook and LinkedIn pages.

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 2015 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 Summary of Product Characteristics for VENCLYXTO.
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⁴ Stilgenbauer S, et al. Understanding and managing ultra high-risk chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2010; 1:481-488.
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⁷ European Medicines Agency. Public summary of opinion on orphan designation. Venetoclax for the treatment of multiple myeloma. http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2016/11/WC500216111.pdf. Accessed November 2016.
⁸ Multiple Myeloma Research Foundation. Learn the basics about multiple myeloma. https://www.themmrf.org/multiple-myeloma/. Accessed October 2016.
⁹ European Medicines Agency. Public summary of opinion on orphan designation. Venetoclax for the treatment of diffuse large B-cell lymphoma. http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2016/11/WC500216112.pdf. Accessed November 2016.
¹⁰ Lymphoma Research Foundation. Diffuse Large B-Cell Lymphoma (DLBCL). http://www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=6300153. Accessed October 2016.
¹¹ European Medicines Agency. Public summary of opinion on orphan designation. Venetoclax for the treatment of acute myeloid leukaemia. http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2016/04/WC500204479.pdf. Accessed October 2016.
¹² National Cancer Institute. Adult Acute Myeloid Leukemia Treatment (PDQ®)—Patient Version. Accessed October 2016. https://www.cancer.gov/types/leukemia/patient/adult-aml-treatment-pdq.
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¹⁴ Clinicaltrials.gov. NCT01889186: A study of the efficacy of ABT-199 in subjects with relapsed or refractory chronic lymphocytic leukemia with the 17p deletion. Accessed October 2016.
¹⁵ Clinicaltrials.gov. NCT01994837: A Phase 2 Study of ABT-199 in subjects with Acute Myelogenous Leukemia (AML). Accessed October 2016.
¹⁶ Clinicaltrials.gov. NCT01794520: Study evaluating ABT-199 in subjects with relapsed or refractory Multiple Myeloma. Accessed October 2016.
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¹⁸ Venclexta [Package Insert]. North Chicago, Ill.: AbbVie Inc.

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