ABBV AbbVie Inc

NORTH CHICAGO, Ill., Dec. 12, 2017 /PRNewswire/ -- AbbVie (NYSE: ABBV), a research and development based global biopharmaceutical company, today announced the first presentation of efficacy and safety results from MURANO, an international, multicenter, open-label, randomized Phase 3 study of VENCLEXTA™/VENCLYXTO™ (venetoclax) in combination with Rituxan® (rituximab) compared with bendamustine in combination with Rituxan in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL). 

Investigator-assessed results showed that patients with R/R CLL achieved significantly prolonged median progression-free survival (PFS) with VENCLEXTA/VENCLYXTO in combination with Rituxan [median PFS, not reached], compared with bendamustine in combination with Rituxan [median PFS, 17.0 months; hazard ratio, 0.17; 95% CI, 0.11–0.25; P<0.0001].¹ Twenty-four month PFS estimates were 84.9 percent and 36.3 percent, respectively.¹ Independent Review Committee (IRC)-assessed PFS showed similar results.¹  Additionally, consistent improvement in PFS was observed across the patient subgroups assessed in the trial, including patients with 17p deletion [hazard ratio 0.14; 95% CI, 0.06–0.33].¹ 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.    

At the time of the interim analysis, safety data were consistent with the known safety profiles of the medicines.¹

"The data from the MURANO trial represents the next evolution in a potential treatment option for patients with relapsed/refractory CLL, an indication for which we received Breakthrough Therapy Designation," said Michael Severino, M.D., executive vice president, research and development, and chief scientific officer, AbbVie. "We are proud to present these findings at the ASH annual meeting and are working closely with regulatory authorities to bring this combination therapy to appropriate patients as soon as possible."

The data also serves as the Phase 3 confirmatory study requested by the U.S. Food and Drug Administration (FDA) when VENCLEXTA was granted accelerated approval on April 11, 2016.² Health authority regulatory submissions of VENCLEXTA/VENCLYXTO in combination with Rituxan are underway.

"This primary analysis of the MURANO trial showed a significant improvement in PFS with VENCLEXTA/VENCLYXTO and Rituxan versus bendamustine and Rituxan, with consistent results in all patient subsets assessed," said John Seymour, M.D., Peter MacCallum Cancer Centre & Royal Melbourne Hospital in Australia and lead investigator of the MURANO trial.  "Based on the efficacy and safety results of this trial, the VENCLEXTA/VENCLYXTO and Rituxan combination has the potential to offer a new chemotherapy-free regimen for patients with relapsed/refractory CLL. We continue to monitor safety and efficacy in trial patients to gain further data and information."

Design and Results of Phase 3 Study Presented at ASH 
A total of 389 patients with R/R CLL who had received one to three prior therapies were enrolled in the international, multicenter, open-label, randomized Phase 3 MURANO study.¹ The study was designed to evaluate the efficacy and safety of VENCLEXTA/VENCLYXTO in combination with Rituxan (194 patients; median age, 64.5 years) compared with bendamustine in combination with Rituxan (195 patients; median age, 66.0 years).¹

For patients receiving VENCLEXTA/VENCLYXTO in combination with Rituxan, a 4-week or 5-week dose ramp-up of VENCLEXTA/VENCLYXTO from 20 to 400 mg daily was used to mitigate potential tumor lysis syndrome (TLS) risk.¹ Beginning at week 6, intravenous (IV) Rituxan was given monthly for six 28-day cycles (375 mg/m² first dose, then 500 mg/m²).¹ Patients continued with VENCLEXTA/VENCLYXTO 400 mg for a maximum of two years or until disease progression, whichever was first.¹ For patients receiving bendamustine in combination with Rituxan, patients were given bendamustine (70 mg/m² IV) on days 1 and 2 of each of six 28-day cycles in combination with Rituxan using the same dosing schedule.¹

The primary endpoint was investigator-assessed PFS, which was determined using standard International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guidelines.³ Secondary endpoints included Independent Review Committee (IRC)-assessed PFS, as well as PFS in patients with 17p deletion, best overall response (defined as complete response [CR], complete response with incomplete marrow recovery [CRi], nodular partial response [nPR], or partial response [PR]), overall survival (OS), event-free survival, duration of response, time to next anti-CLL treatment, and percentage of patients achieving minimal residual disease (MRD)-negativity.³ As of May 8, 2017, median follow-up was 23.8 months (range, 0-37.4 months).¹

Study Results:¹

In the study, the adverse events (AEs) were consistent with the known safety profile of VENCLEXTA/VENCLYXTO and Rituxan. Grade 3-4 neutropenia was higher in the VENCLEXTA/VENCLYXTO in combination with Rituxan arm of the trial. ¹ For patients taking VENCLEXTA/VENCLYXTO in combination with Rituxan and bendamustine in combination with Rituxan, there were 6 (3.1 percent) and 2 (1.1 percent) grade ≥3 TLS AEs reported in each arm, respectively.¹ For VENCLEXTA/VENCLYXTO in combination with Rituxan versus bendamustine in combination with Rituxan, respectively, Richter transformation was confirmed in 6 and 5 patients, and AEs leading to death were seen in 10 (5.2 percent) versus 11 (5.9 percent) patients.¹

Summary of Adverse Events (AEs):¹

About VENCLEXTA™/VENCLYXTO™
VENCLEXTA/VENCLYXTO is an oral B-cell lymphoma-2 (BCL-2) inhibitor that targets a specific protein in the body called BCL-2.^2,5 When you have CLL, BCL-2 may build up and prevent cancer cells from self-destructing naturally.^2,5 VENCLEXTA/VENCLYXTO targets BCL-2 in order to help restore the process of apoptosis.^2,5 Through apoptosis, your body allows cancer cells and normal cells to self-destruct.^2,5

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 with venetoclax, which is currently being evaluated in clinical trials in several hematologic cancers. 

VENCLEXTA/VENCLYXTO is currently approved in 49 nations, including the U.S., and in the EU. 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.

About VENCLYXTO™ (venetoclax) Tablets (EU)
VENCLYXTO™ (venetoclax) is indicated in the European Union (EU) 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.⁵ It is also being evaluated for the treatment of patients with various blood cancer types. ^1,6,7,8,9 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

Important VENCLYXTO (venetoclax) EU Safety Information
Contraindications
Hypersensitivity to the active substance or to any of the excipients. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase. Concomitant use of preparations containing St. John's wort.

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 co-administration 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
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.

Safety in patients with severe renal impairment or on dialysis has not been established, and a recommended dose has not been determined. VENCLYXTO should be administered to patients with severe renal impairment only if the benefit outweighs the risk. Monitor closely for signs of toxicity due to increased risk of TLS.

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 VENCLEXTA™ (venetoclax) tablets (US)
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.² 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.

VENCLEXTA has been granted four Breakthrough Therapy Designations from the FDA including for the combination treatment of patients with untreated AML not eligible for standard induction chemotherapy.  This designation is intended to expedite the development and review of therapies for serious or life-threatening conditions.¹⁰ In January 2016, AbbVie announced that the FDA granted priority review for the single agent NDA application for VENCLEXTA.

In November 2017, AbbVie and Genentech received the Prix Galien award for "Best Pharmaceutical Product" for VENCLEXTA.¹¹

What is VENCLEXTA™ (venetoclax)?
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.

VENCLEXTA was approved based on response rate. There is an ongoing study to find out how VENCLEXTA works over a longer period of time.

It is not known if VENCLEXTA is safe and effective in children.

Important VENCLEXTA™ (venetoclax) US 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. If you are not sure about the type of immunization or vaccine, ask your doctor. These vaccines may not be safe or may not work as well during treatment with VENCLEXTA.
• 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 low white blood cell count, 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.

The full U.S. prescribing information for VENCLEXTA can be found here. Globally, prescribing information varies; refer to the individual country product label for complete information.

Patient Assistance
For those who qualify, patient assistance options are available for people taking VENCLEXTA in the U.S.

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://abbvieoncology.com.

About AbbVie
AbbVie is a global, research-driven 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 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," of AbbVie's 2016 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.

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