On November 1, 2018 AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, reported that the European Commission (EC) has approved the type-II variation application for VENCLYXTO (venetoclax) 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 (Press release, AbbVie, NOV 1, 2018, View Source [SID1234530458]). This approval allows more patients to receive VENCLYXTO in the second-line setting and gives healthcare providers the ability to prescribe this medicine to a broader population of patients with R/R CLL than the previously approved indication for VENCLYXTO as monotherapy in the European Union (EU). The approval is valid in all 28 member states of the EU, as well as Iceland, Liechtenstein and Norway.

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The EC approval is based on results from the MURANO Phase 3 randomized clinical trial, which evaluated the efficacy and safety of VENCLYXTO in combination with rituximab compared to bendamustine in combination with rituximab, an established standard of care chemoimmunotherapy regimen for patients with R/R CLL.1 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) in patients who received VENCLYXTO plus rituximab, resulting in an 83 percent reduction in the risk of disease progression or death (hazard ratio [HR]:0.17; 95% confidence interval [CI]: 0.11-0.25; P<0.0001) and prolonged overall survival (OS) compared to the standard of care chemoimmunotherapy (HR: 0.48; 95% CI: 0.25-0.90; overall survival data are not yet mature).1

In the MURANO Phase 3 clinical trial, undetectable minimal residual disease (uMRD) was a secondary endpoint assessed at the end of combination therapy (nine-month assessment1,3). The majority of patients in the trial who received VENCLYXTO plus rituximab achieved uMRD in the peripheral blood, with 62.4 percent of patients achieving uMRD versus 13.3 percent with bendamustine in combination with rituximab.1 uMRD is an objective measure 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 Earlier prospective clinical trials have provided evidence that achieving uMRD in CLL patients is associated with improved clinical outcomes.2

"Chronic lymphocytic leukemia can relapse and become refractory to first-line treatment, and there is a need for better therapies to treat these patients who otherwise have limited options," 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 venetoclax plus rituximab combination provides these patients with an alternative treatment option that is superior to a type of chemoimmunotherapy and can achieve deep responses, as shown by MRD negativity rates in the peripheral blood and bone marrow, allowing for a fixed duration of treatment without the need for chemoimmunotherapy."

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.4 CLL accounts for approximately one third of new leukemia diagnoses.5

In September 2018, AbbVie announced the European Committee for Medicinal Products for Human Use (CHMP) granted a positive opinion for the Marketing Authorization Application for VENCLYXTO plus rituximab for the treatment of patients with R/R CLL.

"The approval of VENCLYXTO in combination with rituximab is an important step forward in providing patients with relapsed/refractory chronic lymphocytic leukemia a strong chance to live longer without their disease progressing," said Michael Severino, M.D., executive vice president, research and development and chief scientific officer, AbbVie. "We look forward to bringing VENCLYXTO to more patients with chronic lymphocytic leukemia, while continuing to further the research and development of therapies with the potential to transform the standards of care in blood cancers."

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. Median PFS with VENCLYXTO in combination with rituximab was not reached compared with 17.0 months for bendamustine in combination with rituximab (HR: 0.17; 95% CI: 0.11-0.25; P<0.0001). The median follow-up was 23.8 months (range: 0.0 to 37.4). 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

The safety profile of the combination of VENCLYXTO plus rituximab is consistent with the known safety profile of each of the medicines alone. The most common adverse reactions (ARs; ≥20 percent) of any grade for VENCLYXTO in combination with rituximab were neutropenia, diarrhea and upper respiratory tract infection. In the VENCLYXTO in combination with rituximab arm due to any AR, discontinuation occurred in 16 percent of patients, dose reduction in 15 percent, and dose interruption in 71 percent. In the VENCLYXTO in combination with rituximab arm, neutropenia led to dose interruption of VENCLYXTO in 43 percent of patients and discontinuation in 3 percent. The most serious ARs (≥2 percent) for VENCLYXTO in combination with rituximab or VENCLYXTO monotherapy were pneumonia, febrile neutropenia and tumor lysis syndrome.1

About VENCLYXTO (venetoclax)
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/VENCLYXTO 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) EU Safety Information3

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, monitoring, and management for TLS.

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.

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, diarrhea, and upper respiratory tract infection. In the monotherapy studies, the most common adverse reactions were neutropenia/neutrophil count decreased, diarrhea, nausea, anemia, fatigue, and upper respiratory tract infection.

The most frequently occurring serious adverse reactions (>=2%) in patients receiving venetoclax in combination with rituximab or as monotherapy were pneumonia, febrile neutropenia and TLS.

Discontinuation due to adverse reactions occurred in 16% of patients receiving venetoclax plus rituximab and 9% receiving venetoclax monotherapy. Dosage adjustments due to adverse reactions occurred in 15% of patients receiving venetoclax plus rituximab and 2% receiving venetoclax monotherapy. Dose interruptions occurred in 71% of patients treated with the combination of venetoclax and rituximab.

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 nursing women to discontinue breastfeeding during treatment.