AbbVie Announces US FDA Approval of Venclexta (venetoclax) as a Chemotherapy-Free Combination Regimen for Previously Untreated Chronic Lymphocytic Leukemia Patients

In continuation of my update on Venclexta (venetoclax)

AbbVie a research-based global biopharmaceutical  company,  announced that the U.S. Food and Drug Administration (FDA) has approved Venclexta (venetoclax) in combination with obinutuzumab (Gazyva®) for previously untreated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The FDA granted Breakthrough Therapy designation for this combination therapy, and early submission of the data was provided under the Real-Time Oncology Review (RTOR) pilot program, which led to approval in just over two months, following submission of the complete application.

"This FDA approval provides a new chemotherapy-free combination treatment option for patients, and underscores the growing utility of Venclexta in CLL," said Michael Severino, M.D., vice chairman and president, AbbVie.  "The approval is based on findings from the CLL14 trial in which patients received a 12-month treatment regimen. The majority of patients receiving Venclexta in the trial remained progression-free at two years."

Data from the CLL14 trial is expected to be presented at an upcoming medical meeting and published in a journal this year.

"Patients never treated for their CLL have had to rely largely on chemotherapy as their initial treatment," said Michael Hallek, M.D., lead investigator of the CLL14 study, Department of Internal Medicine and Center of Integrated Oncology at the University Hospital Cologne in Germany, and Head of the German CLL Study Group. "The approval of the Venclexta combination means that patients with previously untreated CLL now have a finite duration, chemotherapy-free treatment option that can allow them to live longer without disease progression, induce high rates of minimal residual disease (MRD) negativity and, importantly, allow them to complete their course of therapy within 12 months. This is a major step forward in how previously untreated CLL is managed and further supports the growing benefits offered by Venclexta in CLL."

The CLL14 trial demonstrated superior progression-free survival as assessed by an independent review committee (PFS; the time from initiation of treatment until disease progression or death) in patients treated with Venclexta plus obinutuzumab compared to patients who received chlorambucil plus obinutuzumab, a commonly used standard of care. With a median follow-up of 28 months (range: 0.1 to 36 months), Venclexta plus obinutuzumab reduced the risk of progression or death by 67% compared with chlorambucil plus obinutuzumab (hazard ratio: 0.33, 95% confidence interval [CI]: 0.22, 0.51; p<0.0001).1 Median PFS was not reached in either treatment arm.1  Minimal residual disease (MRD) negativity (undetectable disease in the blood or bone marrow) was assessed as a secondary endpoint and occurs when less than one CLL cell per 10,000 leukocytes can be detected using sensitive analytical methods.  Higher rates of MRD negativity were observed with Venclexta plus obinutuzumab compared to obinutuzumab plus chlorambucil in both bone marrow (57% versus 17%, p<0.0001) and peripheral blood (76% versus 35%, p<0.0001) three months after treatment completion .

In the CLL14 trial, adverse events (AEs) were consistent with the known safety profiles of Venclexta and obinutuzumab alone. Serious adverse reactions (ARs) were reported in 49% of patients in the Venclexta plus obinutuzumab arm, most often due to febrile neutropenia and pneumonia (5% each). The most common ARs (≥15%) of any grade were neutropenia (60%), diarrhea (28%), fatigue (21%), nausea (19%), anemia (17%), and upper respiratory tract infection (17%).

Venclexta, an oral B-cell lymphoma-2 (BCL-2) inhibitor, has been granted five Breakthrough Therapy designations from the FDA.

https://en.wikipedia.org/wiki/Venetoclax

FDA approves combination of Venclexta and Rituxan for lymphocytic leukemia treatment

   

                   

  

Venclexta® (venetoclax)                                           Rituxan® (rituximab)     

In continuation of my update on Venclexta® (venetoclax)  and Rituxan® (rituximab)

Genentech, a member of the Roche Group, announced today that the U.S. Food and Drug Administration (FDA) has approved Venclexta® (venetoclax) in combination with Rituxan® (rituximab) for the treatment of people with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), with or without 17p deletion, who have received at least one prior therapy. Venclexta is being developed by AbbVie and Genentech, a member of the Roche Group. It is jointly commercialized by the companies in the United States and commercialized by AbbVie outside of the United States.

"We are pleased that this approval makes Venclexta, a first of its kind targeted therapy, available for more people with chronic lymphocytic leukemia whose disease has returned after previous treatment," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "Venclexta plus Rituxan provides a new chemotherapy-free option shown to help people live longer without their disease progressing compared to a standard-of-care therapy."

The approval of Venclexta plus Rituxan for people with previously treated CLL is primarily based on the results of the Phase III MURANO study, which were published online in the New England Journal of Medicine in March 2018 and presented at the American Society of Hematology Annual Meeting in December 2017. The results showed that a fixed duration of treatment with Venclexta plus Rituxan significantly reduced the risk of disease progression or death (progression-free survival; PFS) by 81 percent compared with bendamustine plus Rituxan, a current standard of care (HR=0.19; 95 percent CI 0.13-0.28; p<0.0001).

The most common side effects of Venclexta in combination with Rituxan include low white blood cell count, diarrhea, upper respiratory tract infection, cough, fatigue and nausea.

Today's FDA approval converts Venclexta's accelerated approval to a full approval. The FDA has also updated the indication for Venclexta as a single agent, which is now approved for the treatment of people with CLL or SLL, with or without 17p deletion, who have received at least one prior therapy. Venclexta was previously granted accelerated approval in April 2016 as a single agent for the treatment of people with CLL with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy.

The supplemental New Drug Application (sNDA) based on the MURANO data was granted Priority Review, a designation given to medicines that the FDA has determined to have the potential to provide significant improvements in the treatment, prevention or diagnosis of a disease. The FDA also previously granted Breakthrough Therapy Designation for Venclexta in combination with Rituxan for the treatment of relapsed or refractory CLL. Venclexta in combination with Rituxan is recommended in the National Comprehensive Cancer Network (NCCN) guidelines as a treatment option for previously treated CLL (Category 1, Preferred).

An application for a variation of the marketing authorization based on the MURANO data has also been submitted to and validated by the European Medicines Agency (EMA). Additional submissions of the MURANO data to health authorities around the world are ongoing.

https://www.gene.com/media/press-releases/14728/2018-06-08/genentech-announces-fda-approval-for-ven

FDA approves combination of Venclexta and Rituxan for lymphocytic leukemia treatment

BCL-2 inhibitor shows promise in AML patients

In continuation of my update on Venetoclax

Patients whose acute myelogenous leukemia (AML) had relapsed or was resistant to chemotherapy and those who were deemed unable to tolerate chemotherapy experienced responses to the selective BCL-2 inhibitor venetoclax (Venclexta), with complete remissions in some, according to phase II clinical trial data.

Journal in Which the Study was Published: Cancer Discovery, a journal of the American Association for Cancer Research.

Authors: Senior author: Anthony Letai, MD, PhD, associate professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute, in Boston, Massachusetts; Lead author: Marina Konopleva, MD, PhD, professor in the Department of Leukemia and the Department of Stem Cell Transplantation at The University of Texas MD Anderson Cancer Center in Houston

Background: Venetoclax is a small molecule that belongs to a class of drugs called BH3 mimetics. It binds with great affinity and selectivity to BCL-2, an antiapoptotic protein that plays a role in many blood cancers, Letai said. BCL-2 proteins keep the AML cells alive by binding to proapoptotic proteins. Venetoclax binds to BCL-2 and frees the proapoptotic proteins, thus rapidly and irreversibly forcing the AML cell to undergo apoptosis, he explained.

In April 2016, venetoclax was approved by the U.S. Food and Drug Administration for the treatment of certain patients with chronic lymphocytic leukemia (CLL).

How the Study Was Conducted: The study investigators recruited 32 patients with AML with a median age of 71 years to this multicenter, single-arm trial evaluating 800 mg daily oral venetoclax. Twenty-six patients received at least four weeks of therapy.

The investigators performed cytogenetic analysis, BH3 profiling, and next-generation sequencing to look for AML-related genetic mutations in the patients' samples collected at study entry and found that 12 patients had mutations in IDH genes, and six had a high BCL-2-sensitive protein index.

Results: The overall response rate was 19 percent; two patients had complete response (CR) and four had complete response with incomplete blood count recovery (CRi). The median duration of therapy in responders was 144.5 days, and the median duration of CR was 48 days. All patients discontinued therapy due to progressive disease or an adverse event, or for other reasons.

The four patients who had CRi had IDH mutations in their cancer cells. Response to the drug correlated with biomarker results, including indices of BCL-2 protein expression and BH3 profiling, Letai said. "This is significant as it supports the mechanism of action of venetoclax as an on-target inhibitor of BCL-2. Moreover, it offers the possibility of using BH3 profiling as a potential predictive biomarker for clinical use of BH3 mimetics," he added.

FDA Approves Venclexta (venetoclax) for Chronic Lymphocytic Leukemia with 17p Deletion

In continuation of my update on Venclexta

Food and Drug Administration today approved Venclexta (venetoclax) for the treatment of patients with chronic lymphocytic leukemia (CLL) who have a chromosomal abnormality called 17p deletion and who have been treated with at least one prior therapy. Venclexta is the first FDA-approved treatment that targets the B-cell lymphoma 2 (BCL-2) protein, which supports cancer cell growth and is overexpressed in many patients with CLL.

According to the National Cancer Institute, CLL is one of the most common types of leukemia in adults, with approximately 15,000 new cases diagnosed each year. CLL is characterized by the progressive accumulation of abnormal lymphocytes, a type of white blood cell. Patients with CLL who have a 17p deletion lack a portion of the chromosome that acts to suppress cancer growth. This chromosomal abnormality occurs in approximately 10 percent of patients with untreated CLL and in approximately 20 percent of patients with relapsed CLL.

“These patients now have a new, targeted therapy that inhibits a protein involved in keeping tumor cells alive,” said Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “For certain patients with CLL who have not had favorable outcomes with other therapies, Venclexta may provide a new option for their specific condition.”

The efficacy of Venclexta was tested in a single-arm clinical trial of 106 patients with CLL who have a 17p deletion and who had received at least one prior therapy. Trial participants took Venclexta orally every day, beginning with 20 mg and increasing over a five-week period to 400 mg. Results showed that 80 percent of trial participants experienced a complete or partial remission of their cancer.

Venclexta is indicated for daily use after detection of 17p deletion is confirmed through the use of the FDA-approved companion diagnostic Vysis CLL FISH probe kit.

The most common side effects of Venclexta include low white blood cell count (neutropenia), diarrhea, nausea, anemia, upper respiratory tract infection, low platelet count (thrombocytopenia) and fatigue. Serious complications can include pneumonia, neutropenia with fever, fever, autoimmune hemolytic anemia, anemia and metabolic abnormalities known as tumor lysis syndrome. Live attenuated vaccines should not be given to patients taking Venclexta.

The FDA granted the Venclexta application breakthrough therapy designation, priority review status, and accelerated approval for this indication. These are distinct programs intended to facilitate and expedite the development and review of certain new drugs in light of their potential to benefit patients with serious or life-threatening conditions. Venclexta also received orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for exclusivity to assist and encourage the development of drugs for rare diseases.

Venclexta is manufactured by AbbVie Inc. of North Chicago, Illinois, and marketed by AbbVie and Genentech USA Inc. of South San Francisco, California. The Vysis CLL FISH probe kit is manufactured by Abbott Molecular of Des Plaines, Illinois.

FDA Approves Venclexta (venetoclax) for Chronic Lymphocytic Leukemia with 17p Deletion

Novel combination of cancer drugs can have therapeutic impact on diffuse large B-cell lymphoma

In continuation of my update on carfilzomib, JQ1 and ABT 199

New research from Roswell Park Cancer Institute (RPCI) shows that promising cancer drugs used in combination can have significant therapeutic impact on a particularly aggressive subtype of diffuse large B-cell lymphoma (DH-DLBCL) in preclinical studies. The researchers will present their findings at the American Association for Cancer Research (AACR) Annual Meeting 2016, to be held April 16-20 in New Orleans.

Priyank Patel, MD, a fellow in the Department of Medicine at Roswell Park, is the first author and Francisco Hernandez-Ilizaliturri, MD, Clinical Chief of the Institute's Lymphoma/Myeloma Service, is the senior author of "Investigating novel targeted therapies for double hit diffuse large B-cell lymphoma (DH-DLBCL)" (abstract 3038), which will be presented on Tuesday, April 19, at 8 a.m. CDT.

Diffuse large B-cell lymphoma, the most common type of non-Hodgkin lymphoma, is an aggressive form of lymphoma. This research team reviewed a database of 650 patients with diffuse large B-cell lymphoma, identifying 36 patients whose tumors had two or more aberrant genes. Patients with mutations of the c-MYC, BCL2 and/or BCL6 genes — a subtype known as "double-hit lymphoma" — have especially have poor outcomes when treated with standard chemotherapy. The scientists evaluated the effectiveness of three novel anticancer drug candidates that targeted those proteins. In preclinical studies, the therapeutic agents ABT-199, JQ-1 and carfilzomib induced cell death in a dose- and time-dependent manner. Significant synergistic activity was observed when researchers combined ABT199 with carfilzomib and, to a lesser extent, with JQ1 in cancer cell lines.

"Increasing knowledge of genetics and molecular pathways has helped us identify a subgroup of patients who harbor aggressive aberrant gene mutations. Understanding the mechanisms of action and clarifying how these potential therapies work to inhibit cancer cell growth may result in improved outcomes for patients diagnosed with this aggressive type of lymphoma," says Dr. Hernandez-Ilizaliturri.

 Carfilzomib   JQ1  ABT-199

Novel combination of cancer drugs can have therapeutic impact on diffuse large B-cell lymphoma: New research from Roswell Park Cancer Institute shows that promising cancer drugs used in combination can have significant therapeutic impact on a particularly aggressive subtype of diffuse large B-cell lymphoma (DH-DLBCL) in preclinical studies. The researchers will present their findings at the American Association for Cancer Research (AACR) Annual Meeting 2016, to be held April 16-20 in New Orleans.

AbbVie's venetoclax Phase 2 trial meets primary endpoint in patients with relapsed/refractory CLL with 17P deletion

 

AbbVie (NYSE: ABBV), a global biopharmaceutical company, announced that a Phase 2 trial of its investigational medicine
venetoclax met its primary endpoint of achieving overall response ratesin patients with relapsed/refractory or previously untreated chroniclymphocytic leukemia (CLL) with 17p deletion, according to anindependent review analysis. The open-label study evaluated the efficacy and safety of venetoclax, an inhibitor of the B-cell lymphoma-2 (BCL-2)
protein that is being developed in partnership with Genentech and Roche.

Data from this study will be presented at an upcoming medical conference and will serve as the pivotal registration data forapplications to the FDA, EMA and other health authorities. The safety profile was similar to previous studies and no unexpected safety signals were reported for venetoclax.

AbbVie's venetoclax Phase 2 trial meets primary endpoint in patients with relapsed/refractory CLL with 17P deletion

AbbVie's venetoclax Phase 2 trial meets primary endpoint in patients with relapsed/refractory CLL with 17P deletion

Venetoclax, also known as ABT-199 or GDC0199, is an orally bioavailable, selective small molecule inhibitor of the anti-apoptotic protein Bcl-2, with potential antineoplastic activity. Venetoclax mimics BH3-only proteins, the native ligands of Bcl-2 and apoptosis activators, by binding to the hydrophobic groove of Bcl-2 proteins thereby repressing Bcl-2 activity and restoring apoptotic processes in tumor cells. Bcl-2 protein is overexpressed in some cancers and plays an important role in the regulation of apoptosis; its expression is associated with increased drug resistance and tumor cell survival. Compared to the Bcl-2 inhibitor navitoclax, this agent does not inhibit bcl-XL and does not cause bcl-XL-mediated thrombocytopenia....

AbbVie (NYSE: ABBV), a global biopharmaceutical company,  announced that a Phase 2 trial of its investigational medicine venetoclax met its primary endpoint of achieving overall response rates in patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia (CLL) with 17p deletion, according to an independent review analysis. The open-label study evaluated the efficacy and safety of venetoclax, an inhibitor of the B-cell lymphoma-2 (BCL-2) protein that is being developed in partnership with Genentech and Roche.

Data from this study will be presented at an upcoming medical conference and will serve as the pivotal registration data for applications to the FDA, EMA and other health authorities. The safety profile was similar to previous studies and no unexpected safety signals were reported for venetoclax.

AbbVie's venetoclax Phase 2 trial meets primary endpoint in patients with relapsed/refractory CLL with 17P deletion