AbbVie Announces U.S. FDA Approval of VENCLEXTA® (venetoclax tablets) in Combination with Rituximab as a Fixed Duration Treatment for Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Patients Who Have Received One Prior Therapy

-- In the MURANO Phase 3 clinical trial, the VENCLEXTA® (venetoclax tablets) plus rituximab combination showed a significant improvement in progression-free survival (PFS) for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) patients, reducing the risk of disease progression or death by 81 percent when compared to a standard of care chemoimmunotherapy regimen, bendamustine plus rituximab (1)

-- Patients receiving VENCLEXTA plus rituximab achieved a high overall response rate (ORR) of 92 percent (1)

-- With this approval, VENCLEXTA plus rituximab is the first oral-based, chemotherapy-free combination with a fixed treatment duration for CLL

NORTH CHICAGO, IL, USA I June 8, 2018 I AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, today announced the U.S. Food and Drug Administration (FDA) has approved, under priority review, VENCLEXTA® (venetoclax tablets) in combination with rituximab for the treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy.1

The approval is based on MURANO Phase 3 clinical trial data which demonstrated a significant improvement in progression-free survival (PFS) for relapsed/refractory (R/R) CLL patients, reducing the risk of disease progression or death by 81 percent when compared to bendamustine in combination with rituximab, a standard of care chemoimmunotherapy regimen.1

Clinical trial patients who received VENCLEXTA plus rituximab also achieved an overall response rate (ORR) of 92 percent and those who received the chemoimmunotherapy regimen achieved an ORR of 72 percent.1  

The safety profile of the combination is consistent with the known safety profile of VENCLEXTA. The most common adverse reactions (ARs), greater than or equal to 20 percent, with VENCLEXTA in combination with rituximab were neutropenia, diarrhea, upper respiratory tract infection, fatigue, cough and nausea.1

VENCLEXTA plus rituximab is the first oral-based, chemotherapy-free combination in CLL that allows patients an option for fixed treatment duration. 

"VENCLEXTA now gives indicated patients a new opportunity to significantly reduce the risk of their disease progressing, compared to a current standard of care. This combination provides previously treated CLL or SLL patients with a chemotherapy-free, fixed duration treatment allowing patients the ability to stop treatment after approximately two years," said Michael Severino, M.D., executive vice president, research and development, and chief scientific officer, AbbVie. "This is an important step for patients and we look forward to continuing to provide new treatment options for people living with difficult-to-treat blood cancers." 

VENCLEXTA has been granted four Breakthrough Therapy Designations (BTDs) from the FDA including for the combination treatment regimen of VENCLEXTA plus rituximab for patients with R/R CLL.2 The approval of the VENCLEXTA plus rituximab treatment regimen marks the second approval granted under priority review by the FDA for VENCLEXTA. Outside of the U.S., regulatory submissions to and reviews with health authorities are underway.

"The approval of the combination of VENCLEXTA plus rituximab for patients with relapsed/refractory CLL or SLL validates the results seen in the Phase 3 trial, including the significant improvement in progression-free survival over a standard of care comparator arm," said Prof. John Seymour, MBBS, Ph.D., lead investigator of the MURANO study and Director of Cancer Medicine at the Peter MacCallum Cancer Centre & Royal Melbourne Hospital in Australia. "Progression-free survival is considered a gold standard for demonstrating clinical benefit in oncology."

CLL is typically a slow-progressing cancer of the bone marrow and blood in which types of white blood cells called lymphocytes become cancerous and multiply abnormally.3 In the U.S., CLL accounts for more than 20,000 newly diagnosed cases of leukemia each year.3  SLL is closely related to CLL. However, unlike CLL, SLL cancer cells are typically found in the lymph nodes and spleen rather than the bone marrow and the blood. In the U.S., approximately 5,000 cases of SLL are diagnosed annually.4

The FDA has also approved expansion of the indication of VENCLEXTA as monotherapy for CLL or SLL patients, with or without 17p deletion, who have received one prior therapy. Previously, VENCLEXTA, the first B-cell lymphoma-2 (BCL-2) inhibitor in CLL, was approved under accelerated approval in the U.S. in April 2016 as a monotherapy 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.5 VENCLEXTA 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 Study

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 (1:1) MURANO study (NCT02005471). The study was designed to evaluate the efficacy and safety of VENCLEXTA in combination with rituximab (194 patients) compared with bendamustine in combination with rituximab (195 patients). The median age of patients in the trial was 65 years (range 22-85).1 

Efficacy in the U.S. was based on PFS as assessed by an Independent Review Committee (IRC). Median PFS with VENCLEXTA in combination with rituximab was not reached, compared with 18.1 months for bendamustine in combination with rituximab (hazard ratio: 0.19; 95% confidence interval [CI]: 0.13, 0.28; P<0.0001). The median follow-up for PFS was 23.4 months (range: 0 to 37.4+ months). Additional efficacy endpoints included IRC-assessed response rate (defined as ORR, complete response [CR] plus complete response with incomplete marrow recovery [CRi], nodular partial response [nPR], or partial response [PR]) and overall survival (OS).1 

The most common ARs (≥20 percent) of any grade for VENCLEXTA in combination with rituximab were neutropenia (65 percent), diarrhea (40 percent), upper respiratory tract infection (39 percent), fatigue (22 percent), cough (22 percent), and nausea (21 percent). In the VENCLEXTA plus rituximab arm, discontinuations due to any ARs occurred in 16 percent of patients, dose reduction in 15 percent, and dose interruption in 71 percent. In the bendamustine plus rituximab arm, ARs led to treatment discontinuation in 10 percent of patients, dose reduction in 15 percent, and dose interruption in 40 percent. In the VENCLEXTA in combination with rituximab arm, neutropenia led to dose interruption of VENCLEXTA in 46 percent of patients and discontinuations in 3 percent, and thrombocytopenia led to discontinuation in 3 percent of patients. In the VENCLEXTA in combination with rituximab arm, fatal ARs that occurred in the absence of disease progression and within 30 days of the last VENCLEXTA treatment and/or 90 days of last rituximab were reported in 2 percent (4/194) of patients. Serious ARs were reported in 46 percent of patients, with the most frequent (≥5 percent) being pneumonia (9 percent).1

About the Monotherapy Studies

M13-982 (NCT01889186) was a multicenter, open-label, single-arm clinical trial of 106 patients with CLL with 17p deletion who had received at least one prior therapy. The efficacy of VENCLEXTA was evaluated by ORR as assessed by an IRC using the International Workshop for Chronic Lymphocytic Leukemia (iwCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines (2008). The median time on treatment at the time of evaluation was 12.1 months (range: 0 to 21.5 months). Results showed the ORR was 80 percent (95% CI: 71, 87). The CR and CRi rates were 6 percent and 2 percent, respectively; and the nPR and PR rates were 3 percent and 70 percent. Time to first response (TTFR), duration of response (DOR), and MRD-negativity were also evaluated.1

M12-175 (NCT01328626) was a multicenter, open-label study that enrolled previously treated patients with CLL or SLL, including those with 17p deletion. Efficacy was evaluated in 67 patients (59 with CLL, 8 with SLL) according to 2008 iwCLL guidelines. The median duration of treatment at the time of evaluation was 22.1 months (range: 0.5 to 50.1 months). As assessed by an IRC, ORR was 71 percent (95% CI: 58, 82), CR+CRi rate was 7 percent, and PR rate was 64 percent. Based on investigator assessments, the ORR in patients with CLL was 80 percent (14 percent CR+CRi, 66 percent PR+nPR). For the 8 patients with SLL, the investigator assessed ORR was 100 percent.1

M14-032 (NCT02141282) was a multicenter, open-label study that evaluated the efficacy of VENCLEXTA in patients with CLL who had been previously treated with and progressed on or after ibrutinib or idelalisib. Efficacy was evaluated in 127 patients (91 with prior ibrutinib, 36 with prior idelalisib) according to 2008 iwCLL guidelines. At the time of analysis, the median duration of treatment was 14.3 months (range: 0.1 to 31.4 months). Based on IRC assessment, the ORR was 70 percent (95% CI: 61, 78), with a CR+CRi rate of 1 percent, and a PR rate of 69 percent. Based on investigator assessment, the ORR was 65 percent (95% CI: 56, 74).1

Safety was evaluated in a pooled dataset of 352 patients from the three monotherapy studies. Fatal ARs were reported in 2 percent of patients, most commonly (2 patients) from septic shock. Serious ARs were reported in 52 percent of patients, with the most frequent (≥5 percent) being pneumonia (9 percent), febrile neutropenia (5 percent), and sepsis (5 percent). Discontinuations due to ARs occurred in 9 percent of patients, and dose reductions due to ARs occurred in 13 percent of patients. The most common ARs (≥20 percent) any grade were neutropenia (50 percent), diarrhea (43 percent), nausea (42 percent), upper respiratory tract infection (36 percent), anemia (33 percent), fatigue (32 percent), thrombocytopenia (29 percent), musculoskeletal pain (29 percent), edema (22 percent), and cough (22 percent). The most common Grade 3 or 4 ARs (≥5 percent) were neutropenia (45 percent), thrombocytopenia (20 percent), anemia (18 percent), pneumonia (8 percent), lymphopenia (7 percent), and febrile neutropenia (6 percent).1

About VENCLEXTA® (venetoclax tablets) (US)

VENCLEXTA is an oral BCL-2 inhibitor that targets a specific protein in the body called BCL-2.1 When you have CLL or SLL, BCL-2 may build up and prevent cancer cells from self-destructing naturally. VENCLEXTA targets BCL-2 in order to help restore the process of apoptosis.1

VENCLEXTA 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.6, 7, 8, 9 

VENCLEXTA (VENCLYXTO® in the EU) is currently approved as a monotherapy in 53 nations, including the U.S. AbbVie, in collaboration with Roche and Genentech, is currently working with regulatory agencies around the world to bring this medicine to additional eligible patients in need.

In April 2016, the U.S. FDA first granted accelerated approval of VENCLEXTA 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.5 The FDA approved this indication under accelerated approval based on overall response rate.5 With this approval, VENCLEXTA is now approved for the treatment of patients with CLL or SLL, with or without 17p deletion, who have received at least one prior therapy in combination with rituximab or as monotherapy. 1   

VENCLEXTA has been granted four Breakthrough Therapy Designations from the FDA including for the combination treatment regimen of VENCLEXTA plus rituximab for patients with CLL who have received at least one prior therapy.2 This designation is intended to expedite the development and review of therapies for serious or life-threatening conditions.10 The approval of the VENCLEXTA plus rituximab treatment regimen marks the second approval granted under priority review by the FDA for VENCLEXTA. In January 2016, AbbVie announced that the FDA granted priority review for the NDA application for single agent VENCLEXTA.

What is VENCLEXTA® (venetoclax tablets)?
VENCLEXTA is a prescription medicine used to treat people with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with or without 17p deletion, who have received at least one prior treatment.

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

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 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.

References

       
 
1 Venclexta (venetoclax) [Package Insert]. North Chicago, Ill.: AbbVie Inc.
2 Farrell A. Grant-Breakthrough Therapy Designation (CLL). Department of Health and Human Services. 2016:1-3.
3 American Cancer Society (2015). Chronic Lymphocytic Leukemia (CLL).
 http://www.cancer.org/acs/groups/cid/documents/webcontent/003111-pdf.pdf. Accessed June 2018.
4 Seattle Cancer Care Alliance (2018). Chronic Lymphocytic Leukemia Facts. https://www.seattlecca.org/diseases/chronic-lymphocytic-leukemia-cll/cll-facts. Accessed June 2018.
5 U.S. Food and Drug Administration (2016). News and Events: FDA approves new drug for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality.  https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm495253.htm. Accessed June 2018.
6 Clinicaltrials.gov (2018). NCT01994837: A Phase 2 Study of ABT-199 in subjects with Acute Myelogenous Leukemia (AML). Accessed June 2018.
7 Clinicaltrials.gov (2018). NCT01794520: Study evaluating ABT-199 in subjects with relapsed or refractory Multiple Myeloma. Accessed June 2018.
8 Clinicaltrials.gov (2018). 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 June 2018.
9 Clinicaltrials.gov (2018). NCT01889186: A study of the efficacy of ABT-199 in subjects with relapsed/refractory or previously untreated chronic lymphocytic leukemia with the 17p deletion. Accessed June 2018.
10 U.S. Food and Drug Administration (2018). Fact Sheet: Breakthrough Therapies. https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAct/FDASIA/ucm329491.html. Accessed June 2018.

SOURCE: AbbVie

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