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FDA Fast Track Designation Granted to Luspatercept for the Treatment of Patients with Lower-Risk Myelodysplastic Syndromes

On December 7, 2015 Celgene Corporation (NASDAQ:CELG) and Acceleron Pharma Inc. (NASDAQ:XLRN) reported that the United States Food and Drug Administration (FDA) has granted Fast Track Designation to luspatercept for the treatment of anemia in patients with lower-risk myelodysplastic syndromes (MDS) (Press release, Acceleron Pharma, DEC 7, 2015, View Source [SID:1234508446]). The Fast Track program of the FDA is designed to facilitate the development, and expedite the review, of new drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.

Celgene and Acceleron are developing luspatercept to treat patients with rare blood disorders, including MDS and beta-thalassemia. For people with MDS, a type of blood cancer, anemia is a challenging clinical complication of the disease. Patients receive chronic red blood cell transfusions as standard of care to manage the anemia. Luspatercept is designed to increase red blood cell levels in a way that is fundamentally distinct from existing therapies, and has the potential to treat anemia in patients whose disease is not adequately addressed by the treatments available today.

“The FDA’s Fast Track Designation for luspatercept recognizes the serious unmet medical needs of patients with MDS,” said Jacqualyn A. Fouse, President, Hematology/Oncology for Celgene. “Celgene and Acceleron are working to initiate a Phase 3 clinical program to investigate the treatment of patients with low- and intermediate- risk MDS before the end of the year.”

The Companies previously announced FDA Fast Track Designation for luspatercept to treat beta-thalassemia.

About Luspatercept

Luspatercept is a modified activin receptor type IIB fusion protein that acts as a ligand trap for members in the Transforming Growth Factor-Beta (TGF-beta) superfamily involved in the late stages of erythropoiesis (red blood cell production). Luspatercept is thought to regulate late-stage erythrocyte (red blood cell) precursor cell differentiation and maturation. This mechanism of action is distinct from that of erythropoietin (EPO), which stimulates the proliferation of early-stage erythrocyte precursor cells. Acceleron and Celgene are jointly developing luspatercept as part of a global collaboration. Acceleron and Celgene are initiating phase 3 clinical trials that are designed to evaluate the safety and efficacy of luspatercept in patients with myelodysplastic syndromes (the “MEDALIST” study) and in patients with beta-thalassemia (the “BELIEVE” study). For more information, please visit www.clinicaltrials.gov.

About Myelodysplastic Syndromes

MDS comprise a heterogeneous group of hematologic malignancies of the bone marrow commonly leading to severe and chronic anemia due to ineffective erythropoiesis. The National Cancer Institute estimates that more than 10,000 people are diagnosed with MDS in the United States each year. Patients with MDS often have a hypercellular bone marrow with various dysplastic changes of the cells that are also seen in peripheral blood, resulting in cytopenias (low blood cell counts) and an increased risk of progression to acute myeloid leukemia. Nearly all MDS patients suffer from anemia. The anemia in MDS is often characterized by high endogenous levels of EPO driving an abundance of early stage red blood cell precursors and an inability of these precursor cells to properly differentiate into healthy, functional red blood cells. Many patients are therefore unresponsive to the administration of erythropoietin to correct the resulting anemia and instead require red blood cell transfusions, which can increase the risk of infection and iron-overload related toxicities.

Kite Pharma Receives FDA Breakthrough Therapy Designation for KTE-C19 for the Treatment of Refractory, Aggressive Non Hodgkin Lymphoma (NHL)

On December 7, 2015 Kite Pharma, Inc. (Nasdaq:KITE) reported that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation status to the Company’s lead product candidate, KTE-C19, for the treatment of patients with refractory diffuse large B cell lymphoma (DLBCL), primary mediastinal B cell lymphoma (PMBCL), and transformed follicular lymphoma (TFL) (Press release, Kite Pharma, DEC 7, 2015, View Source [SID:1234508441]).

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KTE-C19 is an investigational therapy in which a patient’s T cells are genetically modified to express a chimeric antigen receptor designed to target the antigen CD19, a protein expressed on the cell surface of B cell lymphomas and leukemias.

"The FDA’s designation of KTE-C19 as a breakthrough therapy recognizes the potential for KTE-C19 to address the unmet need for patients with refractory DLBCL, PMBCL, and TFL," noted Arie Belldegrun, M.D., FACS, Chairman, President, and Chief Executive Officer. "We are pleased to receive this designation and look forward to working more closely with the FDA as we continue to advance our program for KTE-C19."

Breakthrough Therapy Designation is granted by the FDA to expedite the development and review of new therapies to treat serious or life-threatening conditions. The criteria for Breakthrough Therapy Designation require preliminary clinical evidence that demonstrates the therapy may have substantial improvement on at least one clinically significant endpoint over available therapy. This designation conveys all fast track program features, as well as more intensive FDA guidance on an efficient drug development program and eligibility for rolling review and priority review.

Pivotal Phase II study showed nearly 80 percent of people with hard-to-treat type of chronic lymphocytic leukaemia responded to investigational medicine venetoclax

On December 7, 2015 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported new, positive data from the Phase II M13-982 study of venetoclax, an investigational medicine being developed in partnership with AbbVie (Press release, Hoffmann-La Roche , DEC 7, 2015, View Source [SID:1234508439]).

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Results of the study showed a clinically meaningful reduction in the number of cancer cells (overall response rate, ORR) in 79.4 percent of people with previously treated (relapsed or refractory) chronic lymphocytic leukaemia (CLL) with 17p deletion. No unexpected safety signals were reported for venetoclax.
"The high response rates, including complete responses, and duration of response demonstrate the potential of venetoclax to help people with this hard-to-treat type of leukaemia," said Sandra Horning, M.D., Chief Medical Officer and Head of Global Product Development. "This is a patient population that has very few treatment options, and we are working with AbbVie to bring this new option to people as quickly as possible."

These pivotal data from the Phase II M13-982 study were featured in the official press program of the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando on Sunday, December 6, and will be presented during the Late-Breaking Abstracts Session on Tuesday, December 8, at 7:30 A.M. EST by Dr. Stephan Stilgenbauer, University of Ulm, Germany (Abstract #LBA6).

The results show:
The study met its primary endpoint, with an ORR of 79.4 percent with venetoclax, as assessed by an independent review committee (IRC). In addition, 7.5 percent of people achieved a complete response with or without complete recovery (complete response without normal blood counts) in the bone marrow (CR/CRi).

Forty-five people had an assessment for minimal residual disease (MRD) in the blood. Notably 18 people (17 percent of the total, 21 percent of responders) achieved MRD-negativity, meaning no cancer could be detected using a specific test. Ten of these 18 people also had bone marrow assessments and six were MRD-negative.

At one year, 84.7 percent of all responses and 94.4 percent of MRD-negative responses were maintained. The one-year progression-free survival (PFS) and overall survival (OS) rates were 72 percent and 86.7 percent, respectively.

No unexpected safety signals were reported. The most common Grade 3-4 adverse events were low white blood cell count (40 percent), low red blood cell count (18 percent), and low platelet count (15 percent). Grade 3 or higher infection occurred in 20 percent of people. Laboratory tumour lysis syndrome was reported in five people; none had clinical consequences.

Data for venetoclax as a monotherapy or in combinations with other medicines across multiple blood cancers, including CLL, non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM) and acute myeloid leukaemia (AML), will also be presented during the ASH (Free ASH Whitepaper) Annual Meeting.

Separately, positive results in people with CLL included in the Phase I M12-175 study of venetoclax were published online today in the New England Journal of Medicine. The findings support the potential of venetoclax monotherapy for people with relapsed or refractory CLL, including those with 17p deletion.

AbbVie has submitted a New Drug Application (NDA) for venetoclax to the U.S. Food and Drug Administration (FDA) under breakthrough therapy designation (BTD), based in part on results of the M13-982 study. Venetoclax received BTD from the FDA earlier this year for the treatment of people with relapsed or refractory chronic lymphocytic leukaemia harbouring the 17p deletion. AbbVie has also submitted a marketing authorization application (MAA) to the European Medicines Agency (EMA). Submissions to other regulatory authorities around the world are planned in 2016.

About Study M13-982
M13-982 (NCT01889186) is a Phase II, open label, single arm, multi-centre study evaluating the efficacy and safety of venetoclax in patients with relapsed, refractory or previously untreated CLL harbouring the 17p deletion. The main study cohort included 107 patients with relapsed or refractory disease (all patients except for one had 17p deletion) and approximately 50 patients with relapsed, refractory or previously untreated disease have been enrolled in the safety expansion cohort. The primary endpoint of the study is overall response rate (ORR) as determined by an independent review committee (IRC), and secondary endpoints include complete response (CR), partial response (PR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). The level of minimal residual disease (MRD) in peripheral blood and/or bone marrow was assessed in a subset of people.

About Study M12-175
M12-175 (NCT01328626) is a Phase I, open-label, multi-centre study of venetoclax in people with relapsed or refractory chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL) or non-Hodgkin’s lymphoma (NHL). The study involved an initial dose-escalation phase, followed by an expanded safety phase. The study enrolled approximately 116 patients with relapsed or refractory CLL or SLL, and approximately 95 patients with relapsed or refractory NHL. The primary endpoints of the study included safety, maximum tolerated dose (MTD) and recommended Phase II dose (RPTD). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), overall survival (OS) and duration of response. The level of minimal residual disease (MRD) in peripheral blood and/or bone marrow was assessed in people with CLL.

About Chronic Lymphocytic Leukaemia (CLL)
CLL is a slow-growing cancer of the blood and bone marrow that is generally considered incurable and is one of the most common adult leukaemias worldwide.1,2 Most cases of CLL (95 percent) start in white blood cells called B-cells.1 In certain cases of CLL, a part of chromosome 17 is lost and along with it an important gene that controls apoptosis called p53.3 The 17p deletion is found in 3 to 10 percent of previously untreated cases and approximately 30 to 50 percent of relapsed or refractory cases.4

About Venetoclax (RG7601, GDC-0199/ABT-199)
Venetoclax is an investigational small molecule designed to selectively bind and inhibit the BCL-2 protein, which plays an important role in a process called apoptosis (programmed cell death). It is believed that blocking BCL-2 may restore the signalling system that tells cancer cells to self-destruct. The BCL-2 protein is linked to the development of resistance in certain blood cancers and is expressed in chronic lymphocytic leukaemia (CLL) and non-Hodgkin’s lymphoma (NHL). In collaboration with AbbVie, venetoclax is being evaluated in a robust development program as a single agent or in combination with other medicines. There are ongoing Phase II and III studies for venetoclax in CLL, and Phase I and II studies are also ongoing in several other blood cancers, including indolent NHL, diffuse large B-cell lymphoma (DLBCL), acute myeloid leukaemia (AML) and multiple myeloma (MM).

BI 836909, a Novel Bispecific T Cell Engager for the Treatment of Multiple Myeloma Induces Highly Specific and Efficacious Lysis of Multiple Myeloma Cells in Vitro and Shows Anti-Tumor Activity in Vivo

BI 836909 is a Bispecific T cell Engager (BiTE), designed to redirect the body’s endogenous T cells towards cells expressing B cell maturation antigen (BCMA) on the cell surface (Presentation, ASH (Free ASH Whitepaper), DEC 6, 2015, View Source [SID:1234510960]).
BCMA is a highly plasma cell specific antigen and shows homogeneous expression on the cell surface of multiple myeloma, plasma cell leukemia and plasmacytoma cells. In normal tissues, BCMA expression is restricted to plasma cells, while other normal tissues do not express BCMA. This highly selective expression pattern makes BCMA an ideal target for T cell redirecting therapy.

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The pharmacological effect of BI 836909 depends on its simultaneous binding to both the CD3 epsilon subunit of the T cell receptor complex on T cells as well as to BCMA on multiple myeloma cells, resulting in the lysis of the BCMA-expressing cells.

In vitro, unstimulated peripheral blood mononuclear cells (PBMCs) were co-cultured with several multiple myeloma cell lines and increasing concentrations of BI 836909, and tumor cell lysis, T cell activation, and induction of cytokine release were assessed. BI 836909 induced dose-dependent redirected lysis of human multiple myeloma cell lines with EC90 values ranging from 16 to 810 pg/mL. Viability of BCMA-negative cells was not affected, demonstrating the specificity of BI 836909 for BCMA. The expression of the activation markers CD69 and CD25 on T cells and the release of cytokines by T cells were target-dependent and occurred only in the presence of BCMA-positive cells.

In vivo anti-tumor activity of BI 836909 was assessed in NOD/SCID mice reconstituted with human T cells and bearing subcutaneous or orthotopic xenografts derived from human multiple myeloma cell lines.

In the subcutaneous NCI-H929 xenograft model, animals were treated with BI 836909 by daily intravenous or subcutaneous bolus injections. Statistically significant dose-dependent anti-tumor activity was observed at doses of 50 µg/kg/day and higher. The efficacy of BI 836909 was comparable after intravenous and subcutaneous administration, when the difference in bioavailability of the different routes was considered.

In an orthotopic L-363 xenograft model, treatment with BI 836909 resulted in a statistically significant prolonged survival at doses of 5 µg/kg/day and higher.

BI 836909 shows comparable cross-reactive binding to both BCMA and CD3 epsilon of human and macaque origin at picomolar and low nanomolar affinities respectively, thus allowing the assessment of pharmacodynamics, pharmacokinetics, and safety in non-human primates. In toxicity studies, cynomolgus monkeys were administered doses of up to 135 µg/kg/day of BI 836909 via continuous intravenous infusion, and up to 405 µg/kg/day via daily subcutaneous injection for up to 28 days. A dose- dependent decrease in plasma cells was observed in the bone marrow of treated animals compared to the vehicle control group, consistent with BCMA expression on cynomolgus monkey plasma cells, this demonstrated the pharmacological activity of BI 836909.

These pre-clinical data demonstrate that BI 836909 is a highly potent, efficacious and BCMA-selective T cell redirecting agent and support clinical testing of BI 836909 in multiple myeloma patients.

Pivotal Phase II Study Showed Nearly 80 Percent of People with Hard-to-treat Type of Chronic Lymphocytic Leukemia Responded to Investigational Medicine Venetoclax

On December 6, 2015 Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), reported new, positive data from the Phase II M13-982 study of venetoclax, an investigational medicine being developed in partnership with AbbVie (Press release, Genentech, DEC 6, 2015, View Source [SID:1234508544]). Results of the study showed a clinically meaningful reduction in the number of cancer cells (overall response rate, OR) in 79.4 percent of people with previously treated (relapsed or refractory) chronic lymphocytic leukemia (CLL) with 17p deletion. No unexpected safety signals were reported for venetoclax.

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Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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"The high response rates, including complete responses and duration of response, demonstrate the potential of venetoclax to help people with this hard-to-treat type of leukemia," said Sandra Horning, M.D., chief medical officer and head of Global Product Development. "This is a patient population that has very few treatment options, and we are working with AbbVie to bring this new option to people as quickly as possible."

These pivotal data from the Phase II M13-982 study were featured in the official press program of the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando on Sunday, December 6, and will be presented during the Late-Breaking Abstracts Session on Tuesday, December 8, at 7:30 A.M. EST by Dr. Stephan Stilgenbauer, University of Ulm, Germany (Abstract #LBA6). The results show:

· The study met its primary endpoint, with an ORR of 79.4 percent with venetoclax, as assessed by an independent review committee (IRC). In addition, 7.5 percent of people achieved a complete response with or without complete recovery (complete response without normal blood counts) in the bone marrow (CR/CRi).

· Forty-five people had an assessment for minimal residual disease (MRD) in the blood. Notably 18 people (17 percent of the total, 21 percent of responders) achieved MRD-negativity, meaning no cancer could be detected using a specific test. Ten of these 18 people also had bone marrow assessments and six were MRD-negative.

· At one year, 84.7 percent of all responses and 94.4 percent of MRD-negative responses were maintained. The one-year progression-free survival (PFS) and overall survival (OS) rates were 72 percent and 86.7 percent, respectively.

· No unexpected safety signals were reported. The most common Grade 3-4 adverse events were low white blood cell count (40 percent), low red blood cell count (18 percent), and low platelet count (15 percent). Grade 3 or higher infection occurred in 20 percent of people. Laboratory tumor lysis syndrome was reported in five people; none had clinical consequences.

Data for venetoclax as a monotherapy or in combinations with other medicines across multiple blood cancers, including CLL, non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM) and acute myeloid leukemia (AML), will also be presented during the ASH (Free ASH Whitepaper) Annual Meeting.

Separately, positive results in people with CLL included in the Phase I M12-175 study of venetoclax were published online today in the New England Journal of Medicine. The findings support the potential of venetoclax monotherapy for people with relapsed or refractory CLL, including those with 17p deletion.

AbbVie has submitted a New Drug Application (NDA) for venetoclax to the U.S. Food and Drug Administration (FDA) under breakthrough therapy designation (BTD), based in part on results of the M13-982 study. Venetoclax received BTD from the FDA earlier this year for the treatment of people with relapsed or refractory CLL harboring the 17p deletion. AbbVie has also submitted a marketing authorization application (MAA) to the European Medicines Agency (EMA). Submissions to other regulatory authorities around the world are planned in 2016.

About Study M13-982

M13-982 (NCT01889186) is a Phase II, open-label, single arm, multicenter study evaluating the efficacy and safety of venetoclax in patients with relapsed, refractory or previously untreated chronic lymphocytic leukemia (CLL) harboring the 17p deletion. The main study cohort included 107 patients with relapsed or refractory disease (all patients except for one had 17p deletion) and approximately 50 patients with relapsed, refractory or previously untreated disease have been enrolled in the safety expansion cohort. The primary endpoint of the study is overall response rate (ORR) as determined by an independent review committee (IRC), and secondary endpoints include complete response (CR), partial response (PR), duration of response (DOR), progression-free survival (PFS) and overall survival (OS). The level of minimal residual disease (MRD) in peripheral blood and/or bone marrow was assessed in a subset of patients.

About Study M12-175

M12-175 (NCT01328626) is a Phase I, open-label, multicenter study of venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) or non-Hodgkin’s lymphoma (NHL). The study involved an initial dose-escalation phase, followed by an expanded safety phase. The study enrolled approximately 116 patients with relapsed or refractory CLL or SLL, and approximately 95 patients with relapsed or refractory NHL. The primary endpoints of the study included safety, maximum tolerated dose (MTD) and recommended Phase II dose (RPTD). Secondary endpoints included progression-free survival (PFS), overall response rate (ORR), overall survival (OS) and duration of response (DOR). The level of minimal residual disease (MRD) in peripheral blood and/or bone marrow was assessed in patients with CLL.

About Chronic Lymphocytic Leukemia (CLL)

CLL is one of the most common forms of blood cancer and in 2015, it is expected that there will be about 4,650 deaths from CLL in the United States. Most cases of CLL (95 percent) start in white blood cells called B-cells that have a protein called CD20 on their surface. In certain cases of CLL, a part of chromosome 17 is lost and along with it an important gene that controls apoptosis called p53. The 17p deletion is found in 3 to 10 percent of previously untreated cases and approximately 30 to 50 percent of relapsed or refractory cases.

About Venetoclax (RG7601, GDC-0199/ABT-199)

Venetoclax is an investigational small molecule designed to selectively bind and inhibit the BCL-2 protein, which plays an important role in a process called apoptosis (programmed cell death). It is believed that blocking BCL-2 may restore the signaling system that tells cancer cells to self-destruct. The BCL-2 protein is linked to the development of resistance in certain blood cancers and is expressed in chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL). In collaboration with AbbVie, venetoclax is being evaluated in a robust development program as a single agent or in combination with other medicines. There are ongoing Phase II and III studies for venetoclax in CLL, and Phase I and II studies are also ongoing in several other blood cancers, including indolent NHL, diffuse large B-cell lymphoma (DLBCL), acute myeloid leukemia (AML) and multiple myeloma (MM).