AbbVie Receives Positive CHMP Opinion for VENCLYXTO® as a Chemotherapy-Free Combination Regimen for Patients with Previously Untreated Chronic Lymphocytic Leukemia

- If approved by the European Commission (EC), VENCLYXTO® plus obinutuzumab would be the first chemotherapy-free, combination regimen given with a fixed duration for patients with previously untreated chronic lymphocytic leukemia (CLL)

- Represents third positive CHMP opinion for VENCLYXTO; further supports the growing utility of the therapy across multiple lines of CLL

- Positive opinion based on data from Phase 3 CLL14 trial, which showed that patients who completed one year of treatment with VENCLYXTO plus obinutuzumab had prolonged progression-free survival and higher rates of minimal residual disease negativity compared to patients receiving a standard of care chemoimmunotherapy regimen of obinutuzumab and chlorambucil [1]

News provided by

AbbVie

Jan 31, 2020, 06:55 ET

NORTH CHICAGO, Ill., Jan. 31, 2020 /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) in combination with obinutuzumab for the treatment of patients with chronic lymphocytic leukemia (CLL) who were previously untreated. The positive CHMP opinion is a scientific recommendation for marketing authorization to the European Commission (EC), which is expected to deliver its final decision in the first half of 2020.

"The positive CHMP opinion for this new indication in chronic lymphocytic leukemia is an important step forward for patients and underscores the growing utility of VENCLYXTO in treating this common blood cancer," said Neil Gallagher, M.D., Ph.D., chief medical officer and vice president of development. "If approved by the EC, the venetoclax and obinutuzumab combination would be the first chemotherapy-free option for treatment-naïve patients with chronic lymphocytic leukemia where dosing can be completed in one year."

The CHMP positive opinion is based on results from the Phase 3 CLL14 clinical trial, which evaluated the efficacy and safety of VENCLYXTO in combination with obinutuzumab compared with chlorambucil in combination with obinutuzumab. The primary endpoint was progression-free survival (PFS; the time on treatment without disease progression or death) as assessed by an investigator. At the time of analysis, investigator-assessed results demonstrated that patients treated with VENCLYXTO plus obinutuzumab achieved superior PFS compared to patients treated with obinutuzumab plus chlorambucil. Adverse events were consistent with the known safety profiles of venetoclax and obinutuzumab alone. At least one AE of any grade occurred in 94.3 percent of patients in the venetoclax combination arm, with the most common Grade 3/4 AEs in patients being febrile neutropenia and infections. Tumor lysis syndrome (TLS) was reported in three patients in the venetoclax plus obinutuzumab group (all during treatment with obinutuzumab and before venetoclax).¹ Results from the CLL14 trial were presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting and published in the New England Journal of Medicine.

"Chemotherapy has historically been the first treatment for patients with chronic lymphocytic leukemia. If the venetoclax plus obinutuzumab combination is approved in the EU, previously-untreated patients will, for the first time, have a chemotherapy-free, fixed-duration treatment option," said Michael Hallek, M.D., lead investigator of the CLL14 study, Director of the Department of Internal Medicine and Center of Integrated Oncology Cologne-Bonn at the University Hospital Cologne in Germany, and Head of the German CLL Study Group. "The early use of venetoclax plus obinutuzumab combination has the potential to change the treatment paradigm for chronic lymphocytic leukemia as it has been demonstrated to improve outcomes, allowing patients to live longer without disease progression."

In 2018, the EC approved VENCLYXTO plus rituximab for the treatment of patients with relapsed or refractory (R/R) CLL. VENCLYXTO monotherapy was previously approved in the EU for 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.

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 Chronic Lymphocytic Leukemia
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. CLL is the most common form of leukemia in the Western Hemisphere, accounting for approximately one third of new leukemia diagnoses.^2,3

About the CLL14 Trial
The randomized, multicenter, open-label, actively controlled Phase 3 CLL14 trial, which was conducted in close collaboration with the German CLL Study Group (DCLLSG), evaluated the efficacy and safety of a combined regimen of VENCLYXTO and obinutuzumab (n=216) versus obinutuzumab and chlorambucil (n=216) in patients with previously-untreated CLL and coexisting medical conditions (total Cumulative Illness Rating Scale [CIRS] score >6 or creatinine clearance <70 mL/min). The therapies were administered for a fixed duration of 12 cycles for VENCLYXTO in combination with six cycles of obinutuzumab. Cycles were comprised of 28 days. The trial enrolled 432 patients, all of whom were diagnosed according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria and were previously untreated. The primary efficacy outcome was PFS as assessed by the investigator.¹

Key secondary endpoints were MRD negativity in peripheral blood and bone marrow, and overall and complete response rates.¹

About VENCLYXTO^® (venetoclax tablets)
VENCLYXTO^® 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. VENCLYXTO targets the BCL-2 protein and works to restore the process of apoptosis.

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.

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) EU Indication and Safety Information⁴

Indication
VENCLYXTO in combination with rituximab is indicated for the treatment of adult patients with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy.

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

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
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 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.

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 in patients receiving venetoclax in the combination study with rituximab were neutropenia, diarrhoea, and upper respiratory tract infection. In the monotherapy studies, the most common adverse reactions were neutropenia/neutrophil count decreased, diarrhoea, nausea, anaemia, fatigue, and upper respiratory tract infection.

The most frequently reported serious adverse reactions (≥2%) in patients receiving venetoclax in combination with rituximab were pneumonia, febrile neutropenia, and TLS. In the monotherapy studies, the most frequently reported serious adverse reactions (≥2%) were pneumonia and febrile neutropenia.

Discontinuations due to adverse reactions occurred in 16% of patients treated with the combination of venetoclax and rituximab in the MURANO study. In the monotherapy studies with venetoclax, 11% of patients discontinued due to adverse reactions.

Dosage reductions due to adverse reactions occurred in 15% of patients treated with the combination of venetoclax and rituximab in the MURANO study and 14% of patients treated with venetoclax in the monotherapy studies.

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.

For patients with severe (Child-Pugh C) hepatic impairment, a dose reduction of at least 50% throughout treatment is recommended.

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. AbbVie's oncology portfolio now consists of marketed medicines and a pipeline containing multiple new molecules being evaluated worldwide in more than 300 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, competition from other products, challenges to intellectual property, 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 2019 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 Fischer K, et al. Effect of fixed-duration venetoclax plus obinutuzumab (VenG) on progression-free survival (PFS), and rates and duration of minimal residual disease negativity (MRD–) in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities. Presented at the 2019 American Society of Clinical Oncology Annual Meeting: June 4, 2019; Chicago.
² NCI dictionary. NCI Dictionary of Terms. Chronic Lymphocytic Leukemia. https://www.cancer.gov/publications/dictionaries/cancer-terms. Accessed January 2020.
³ 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 January 2020.
⁴ Summary of Product Characteristics for VENCLYXTO. Ludwigshafen, Germany: AbbVie Deutschland GmbH & Co. KG.