AbbVie Receives Positive CHMP Opinion for a Novel, Chemotherapy-free Combination of VENCLYXTO® (venetoclax tablets) with Rituximab as a Treatment with a Fixed Duration for Patients with Chronic Lymphocytic Leukemia Who Have Received at Least One Prior Therapy

NORTH CHICAGO, Ill., Sept. 21, 2018 /PRNewswire/ -- AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, announced today that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has granted a positive opinion for VENCLYXTO^® (venetoclax tablets) in combination with rituximab for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) who have received at least one prior therapy. The positive CHMP opinion is a scientific recommendation for marketing authorization to the European Commission (EC), which will deliver its final decision, valid in all 28 member states of the European Union, as well as Iceland, Liechtenstein and Norway.

In 2016, VENCLYXTO was approved by the EC as a monotherapy for the treatment of R/R 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. If approved by the EC, VENCLYXTO plus rituximab could be prescribed to a broader patient population with R/R CLL than the currently approved indication for VENCLYXTO monotherapy in the EU.

"This positive CHMP opinion is one important step forward as AbbVie continues to further the research and development of novel medicines with the potential to transform the standard of care in blood cancers," said Michael Severino, M.D., executive vice president, research and development and chief scientific officer, AbbVie. "The combination of VENCLYXTO with rituximab has the potential to give patients with relapsed/refractory chronic lymphocytic leukemia a chance to live longer without their disease progressing, and to stop treatment after their two-year course."

The CHMP positive opinion is based on results from the MURANO Phase 3 clinical trial, which evaluated the efficacy and safety of VENCLYXTO in combination with rituximab compared with bendamustine in combination with rituximab. At the time of the primary analysis, the trial demonstrated a statistically significant improvement in investigator-assessed progression-free survival (PFS; the time on treatment without disease progression or death²) for patients who received VENCLYXTO plus rituximab compared with bendamustine plus rituximab.¹

In the MURANO clinical trial, undetectable minimal residual disease (uMRD), also known as minimal residual disease negativity (MRD-) was a secondary endpoint assessed at the end of combination therapy (nine-month assessment). The majority of patients in the trial who received VENCLYXTO plus rituximab achieved uMRD in the peripheral blood.¹ Undetectable minimal residual disease, is defined as the presence of less than one CLL cell in 10,000 white blood cells remaining in the blood or bone marrow following treatment.²

"The venetoclax plus rituximab combination has the potential to be truly transformative for patients with relapsed/refractory CLL," said Prof. John Seymour, MBBS, Ph.D., lead investigator of the MURANO trial and Director of Cancer Medicine at the Peter MacCallum Cancer Centre & Royal Melbourne Hospital in Australia. "The progression-free survival observed in the MURANO trial, and the fixed duration of treatment that may allow patients to stop treatment, are encouraging developments with the potential to advance the care and management of patients with relapsed/refractory CLL."

CLL is a slow-growing form of leukemia, or blood cancer, in which too many immature lymphocytes (a type of white blood cell) are found predominantly in the blood and bone marrow.³ CLL accounts for approximately one third of new leukemia diagnoses.⁴

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. 

About the MURANO Trial
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, Phase 3 MURANO trial. The trial was designed to evaluate the efficacy and safety of VENCLYXTO in combination with rituximab (N=194) compared with bendamustine in combination with rituximab (N=195). The median age of patients in the trial was 65 years (range: 22-85).¹

The primary efficacy endpoint was investigator (INV)-assessed PFS. Additional efficacy endpoints included independent review committee (IRC)-assessed PFS, INV- and IRC-assessed overall response rate (defined as complete response + complete response with incomplete marrow recovery + partial response + nodular partial response), overall survival, and rates of uMRD.¹

About VENCLYXTO^® (venetoclax tablets)  
VENCLEXTA^® (VENCLYXTO^® in the EU) 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.

VENCLEXTA/ 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 and to studying venetoclax in clinical trials across several blood and other cancers. 

VENCLEXTA/VENCLYXTO is approved in more than 50 countries, including the U.S. AbbVie and Roche are currently working with regulatory agencies around the world to bring this medicine to additional eligible patients in need.

Important VENCLYXTO (venetoclax tablets) EU Safety Information⁵

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.  Serious infections including events of sepsis with fatal outcome have been reported. Supportive measures including antimicrobials for any signs of infection should be considered.

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.

Coadministration 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 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, LinkedIn or Instagram.

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 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.
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 September 2018.
⁴ World Health Organization. 2014 Review of Cancer Medicines on the WHO List of Essential Medicines. http://www.who.int/selection_medicines/committees/expert/20/applications/CLL.pdf. Accessed September 2018.
⁵ Summary of Product Characteristics for VENCLYXTO. Ludwigshafen, Germany: AbbVie Deutschland GmbH & Co. KG.

SOURCE AbbVie

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