AbbVie Announces New Undetectable Minimal Residual Disease Data from Phase 3 Relapsed/Refractory Chronic Lymphocytic Leukemia MURANO Trial of Venetoclax in Combination with Rituximab at 23rd European Hematology Association Annual Congress

NORTH CHICAGO, Ill., June 15, 2018 /PRNewswire/ -- AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, today announced the presentation of investigational data from a new analysis of undetectable minimal residual disease (uMRD) rates from the pivotal Phase 3 MURANO trial of venetoclax, a first-in-class oral B-cell lymphoma-2 (BCL-2) inhibitor, in combination with rituximab (VenR) in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL). Of the 121 patients who achieved uMRD (meaning less than one CLL cell in 10,000 white blood cells were detectable using a standardized test²) at the end of combination therapy (EOCT), 83 percent (n=100) maintained uMRD and were progression-free for a median of 13.8 months (range, 5.6-23.0 months) thereafter. These results will be presented in an oral session on Saturday, June 16, at 11:45 a.m. CEST during the 23^rd European Hematology Association (EHA) Annual Congress in Stockholm.¹  Venetoclax 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.

CLL is a slow-growing form of leukemia, or blood cancer, in which too many immature lymphocytes (type of white blood cells) are found predominantly in the blood and bone marrow.³ Undetectable minimal residual disease is an objective measure defined by the presence of less than one CLL cell in 10,000 white blood cells remaining in the blood or bone marrow following treatment.² Prospective clinical trials have suggested that achieving undetectable minimal residual disease, also known as MRD negativity (MRD-), may have a prognostic impact on response duration and survival outcomes.⁴

"In this analysis of MRD data in patients with chronic lymphocytic leukemia given venetoclax in combination with rituximab, high and durable undetectable MRD rates were achieved in peripheral blood at the end of combination treatment assessment regardless of the risk features," said Peter Hillmen, Ph.D., Professor of Experimental Hematology, Leeds Teaching Hospital in the UK, and lead investigator of the MURANO study. "These undetectable MRD results, along with data regarding the nearly 14-month progression-free findings in patients who maintained undetectable MRD, are an encouraging finding from the MURANO study."

"The venetoclax data being presented at EHA adds to the growing body of evidence that supports a correlation between undetectable minimal residual disease (MRD) and improved clinical outcomes for patients with chronic lymphocytic leukemia," said Neil Gallagher, M.D., Ph.D., Head of Global Oncology Development, AbbVie. "We continue to investigate the correlation between undetectable MRD and clinical outcomes following treatment with venetoclax alone, or in novel combinations, for the potential treatment of patients with chronic lymphocytic leukemia and other blood cancers."

Design and Results of the Phase 3 Study
The international, multicenter, open-label, randomized Phase 3 MURANO study included a total of 389 patients with R/R CLL who had received at least one prior therapy. The study was designed to evaluate the efficacy (primary endpoint of investigator-assessed progression-free survival) and safety of venetoclax in combination with rituximab (194 patients; median age 64.5 years) for up to two years compared with bendamustine in combination with rituximab (195 patients; median age 66.0 years) for six months.⁵

Summary of EHA Presentation
In the analysis, MRD by peripheral blood (PB) samples were serially collected (including EOCT, month 9; and every 12 weeks thereafter for up to three years⁵) whereas bone marrow (BM) samples were collected at the EOCT or at best response. MRD was analyzed centrally by allele-specific oligonucleotide-PCR and/or flow cytometry.¹

A high PB/BM MRD concordance was seen with VenR in patients with paired samples (84 percent). Achievement of uMRD was independent of risk factors, including del(17p), IgVH mutation and TP53 mutations. Eighty-three percent of VenR patients who attained uMRD at EOCT maintained this status and were progression-free for a median of 13.8 months (range, 5.6-23.0 months) after EOCT.¹ 

About VENCLYXTO® (venetoclax) 
VENCLYXTO® (venetoclax), an oral B-cell lymphoma-2 (BCL-2) inhibitor, is indicated for the treatment of chronic lymphocytic leukemia (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.⁶ It is also being evaluated for the treatment of patients with various blood cancer types.^5,7,8,9,10 The BCL-2 protein prevents apoptosis (programmed cell death) of some cells, including lymphocytes, and can be overexpressed in CLL cells.⁵ VENCLYXTO, which is given once-daily, is designed to selectively inhibit the function of the BCL-2 protein.⁵ 

VENCLYXTO 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 Phase 3 clinical trials for the treatment of relapsed/refractory CLL, along with studies in several other cancers.

Venetoclax is currently approved in the European Union, Switzerland, Argentina, Australia, Mexico, Puerto Rico, Israel, USA, 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.

For more information on B-cell lymphoma-2 (BCL-2), please read "Bringing Death to Cancer Cells" on www.abbvie.com.

Important VENCLYXTO (venetoclax) EU Safety Information

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

Special Warnings & Precautions for Use 
Tumor lysis syndrome (TLS), including fatal events, has occurred in patients with previously treated CLL with high tumor burden when treated with VENCLYXTO. VENCLYXTO poses a risk for TLS in the initial 5-week dose-titration phase. Changes in electrolytes 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 IV hydration, frequent monitoring and 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 due to increased risk for TLS 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.  These agents may decrease venetoclax plasma concentrations.

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, diarrhea, 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 
Patients with reduced renal function (CrCl <80 mL/min) may require more intensive prophylaxis and monitoring to reduce the risk of TLS.  Safety in patients with severe renal impairment (CrCl <30 mL/min) or on dialysis has not been established, and a recommended dose for these patients has not been determined. VENCLYXTO should be administered to patients with severe renal impairment only if the benefit outweighs the risk and patients should be monitored closely for signs of toxicity due to increased risk of TLS.

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

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.

¹ Hillmen P, et al. High, durable minimal residual disease negativity with venetoclax + rituximab in relapsed/refractory chronic lymphocytic leukemia: minimal residual disease kinetics and responses in cytogenetic risk groups in patients from the Phase 3 MURANO Study. Presented at the 2018 European Hematology Association Congress; June 16, 2018; Stockholm.
² Hallek M, Cheson BD, Catovsky D, et al.  Guidelines for diagnosis, indications for treatment, response assessment and supportive management of chronic lymphocytic leukemia. Blood. 2018;806398. 
³ NCI dictionary. NCI Dictionary of Terms. Chronic Lymphocytic Leukemia. https://www.cancer.gov/publications/dictionaries/cancer-terms. Accessed May 2018.
⁴ Eichhorst B, Robak T, Montserrat E, et al. Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(suppl 5):v78-v84.
⁵ Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120.
⁶ Summary of Product Characteristics for VENCLYXTO.
⁷ 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 May 2018.
⁸ Clinicaltrials.gov. NCT01994837: A Phase 2 study of ABT-199 in subjects with acute myelogenous leukemia (AML). Accessed May 2018.
⁹ Clinicaltrials.gov. NCT01794520: Study evaluating ABT-199 in subjects with relapsed or refractory multiple myeloma. Accessed May 2018.
¹⁰ Clinicaltrials.gov. 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 May 2018.

SOURCE AbbVie

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