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.

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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"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).

On December 06, 2015 TG Therapeutics, Inc. (Nasdaq:TGTX), reported updated clinical results from its ongoing Phase I proprietary combination study of TG-1101 (ublituximab), the Company’s novel, glycoengineered monoclonal antibody and TGR-1202, the Company’s oral, once-daily, PI3K delta inhibitor as well as data from the Phase I study of TGR-1202 in combination with obinutuzumab plus chlorambucil (Press release, TG Therapeutics, DEC 6, 2015, View Source [SID:1234508445]). Data from these Phase I studies were presented this weekend at poster sessions during the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition being held at the Orange County Convention Center in Orlando, FL.

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Michael S. Weiss, the Company’s Executive Chairman and Interim CEO commented on the data, "We and our clinical investigators continue to be impressed with the activity and safety profile of our proprietary TG-1303 regimen with almost all CLL patients responding and over 70% of heavily pre-treated patients with indolent lymphoma responding to 1303. We are also very excited by the data in patients with large cell lymphoma where we are seeing 35% response rates in heavily pre-treated patients. Collectively, we believe these data support advanced clinical studies for TG-1303 across CLL and NHL and, accordingly, we plan to expand our UNITY clinical program into NHL in 2016. Finally, we are excited to see the high level of activity of a TGR-1202 based regimen in front-line CLL. We believe the safety and efficacy profile observed in those front-line patients sets the stage for what we should expect to see from TG-1303 in front-line patients included in our UNITY-CLL Phase 3 trial, which should open for enrollment in the coming weeks." Mr. Weiss continued, "We appreciate the strong support of our clinical investigators and thank them and their patients for participating in these important clinical trials."

Dr. Matthew Lunning, Assistant Professor, Division of Hematology at the University of Nebraska Medical Center and lead author for the poster presentation stated, "The principal goal for any novel-novel combination study is to establish safety and combinability of two agents. With the combination of ublituximab and TGR-1202, patients were not only able to achieve high response rates and durable remissions, but most importantly, were able to stay on treatment with limited discontinuations due to adverse events, which has been commonly seen with other novel targeted agents in this class. Many of the patients enrolled onto this study have been heavily pre-treated with limited treatment options, especially patients with DLBCL, and the ability to offer patients a novel-novel combination which has the potential to extend and improve patient lives is of great excitement."

The following summarizes the posters presented this weekend:

Ublituximab + TGR-1202 Demonstrates Activity and Favorable Safety Profile in Relapsed/Refractory B-Cell NHL and High-Risk CLL: Phase I Results (Abstract Number 1538)

This poster was presented yesterday, Saturday December 5th during the ASH (Free ASH Whitepaper) Annual Meeting and included data from patients with relapsed and refractory NHL and high-risk CLL treated with the combination of TG-1101 (ublituximab) and TGR-1202. The combination has been well tolerated in the 71 patients evaluable for safety at all dose levels up through 1200mg micronized. This was a heavily pretreated population with high-risk features, including 58% refractory to last treatment with multiple previous lines of rituximab based therapy. Efficacy data was presented on patients treated at the higher doses of TGR-1202 (1200mg of the original formulation and 600mg or greater of the micronized formulation).

Highlights from this poster include:

80% (8 of 10) ORR in patients with CLL/SLL, including 1 CR and 7 PRs
Remaining 2 patients had stable disease, one of which remains on study and the other, an ibrutinib refractory patient, progressed after 2 cycles

75% of CLL patients had high-risk cytogenetics (17p and/or 11q del)
Data supports the current Phase 3 UNITY-CLL Study of TG-1101 + TGR-1202 in CLL

71% (12 of 17) ORR in heavily pretreated patients with indolent NHL (FL & MZL), including 4 CRs (24%) and 8 PRs, with 4 of the remaining 5 patients achieving stable disease

35% (6 of 17) ORR in patients with DLBCL and Richter’s Transformation, 3 of which achieved a CR, with 2 additional patients achieving stable disease

94% of DLBCL patients were refractory to prior therapy with 69% of patients rituximab refractory, including one patient with triple hit lymphoma

Of the 16 DLBCL patients, 9 were GCB subtype, 3 were ABC subtype, and 4 patients’ subtype was unknown, with notable activity (ORR and PFS) observed in patients with confirmed GCB subtype

Combination of 1303 was well tolerated, with only 8% of patients discontinuing due to an adverse event:
Notably, the only Grade 3/4 adverse event occurring in > 5% of patients was neutropenia. Of the 71 patients available for safety, only 6 patients (8%) discontinued due to a TGR-1202 related event

Twenty-six patients have been on the combination of TG-1101 plus TGR-1202 for 6+ months, with no events of colitis reported to date

Safety profile supports multi-drug regimens
A Phase I Trial of TGR-1202, a Next Generation Once Daily PI3K-Delta Inhibitor in Combination with Obinutuzumab Plus Chlorambucil, in Patients with Chronic Lymphocytic Leukemia (Abstract Number 2942)

The poster was presented today, Sunday December 6th during the ASH (Free ASH Whitepaper) Annual Meeting and includes data from patients with treatment naïve and previously treated CLL treated with TGR-1202 in combination with the glycoengineered anti-CD20 mAb, obinutuzumab, and chlorambucil. The study design evaluated escalating doses of TGR-1202 which was dosed orally once-daily starting at Day 1 of Cycle 1. Obinutuzumab and chlorambucil were administered according to their FDA labeled dosing regimen. The combination was dosed in 18 patients, of which 15 were treatment naïve and 3 were previously treated. All patients were evaluable for safety and efficacy.

Highlights from this poster include:

100% (15 of 15) ORR in treatment naïve CLL patients, with 33% of patients achieving a CR, and 47% of patients achieving MRD negativity

95% (17 of 18) ORR in treatment naïve and relapsed/refractory CLL patients, with 28% of patients achieving a CR
Remaining patient achieved a 45% nodal reduction and remains on study, progression-free

Notably, all previously treated CLL patients were refractory to a prior BTK inhibitor and had at least one high-risk cytogenetic abnormality

The combination demonstrated acceptable tolerability, which notably differed from that observed when TGR-1202 was combined with TG-1101 in patients with relapsed or refractory CLL, specifically regarding neutropenia (78% vs. 30%), thrombocytopenia (78% vs. < 10%), and transaminase elevations (39% vs. 8%)

The median PFS has not been reached, with the longest patient on study now 20+ months on TGR-1202 daily maintenance at 800mg

POSTER Presentation details

A copy of the poster presentations are available on the Company’s website at www.tgtherapeutics.com, located on the Publications Page, within the Pipeline section.