Thursday, April 23, 2015

Drugs in Clinical Pipeline: ABT-199

 ABT-199 [4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1H-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide] is a selective, potent, orally bioavailable small molecule  B cell CLL/lymphoma 2 (BCL-2) inhibitor. ABT-199 has demonstrated pre-clinical efficacy inhibiting the growth of AML cell lines or AML-patient derived primary cells systemically engrafted into immunocompromised mice.

GDC-0199/ABT-199, also known as RG7601, is a novel small molecule being developed by AbbVie. Venetoclax is being developed in collaboration with Genentech in the United States and Roche outside the United States. Together, the companies are pioneering BCL-2 research with venetoclax, which is currently being evaluated in a Phase 3 clinical trial for the treatment of CLL and several other cancers.

Common Name: ABT-199
Synonyms: ABT-199; ABT199; ABT 199; GDC-0199; GDC0199; GDC 0199; RG7601; RG-7601; RG 7601; Venetoclax
IUPAC Name: 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide
CAS Number: 1257044-40-8
Mechanism of Action: BCL-2 Inhibitor; B cell CLL/lymphoma 2 Inhibitor
Indication: Various Cancers
Development Stage: Phase III
Company: AbbVie and Genentech/Roche

ABT-199 is a Bcl-2-selective inhibitor with Ki of  less than 0.01 nM, more than 4800-fold more selective versus Bcl-xL and Bcl-w, and no activity to Mcl-1. ABT-199 shows less sensitivity to Bcl-xL, Mcl-1 and Bcl-w with Ki of 48 nM, > 444 nM and 245 nM, respectively. ABT-199 potently inhibits FL5.12-Bcl-2 cells, RS4-11 cells with EC50 of 4 nM and 8 nM, while shows low activity against FL5. Quantitative immunoblotting reveals that sensitivity to ABT-199 correlated strongly with the expression of Bcl-2, including NHL, DLBCL, MCL, AML and ALL cell lines. ABT-199 also induces apoptosis in CLL with an average EC50 of 3.0 nM [1]. 

Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. BCL-2 has been implicated in hematologic malignancies and associated with drug resistance and poor prognosis in acute myelogenous leukemia (AML). These proteins are expressed at high levels in non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and in other B-cell neoplasms. Patients with relapsed/refractory (R/R) AML have poor prognosis with limited overall survival.

The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-XL), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-XL inhibition limits the efficacy achievable with this agent. The re-engineering of navitoclax created a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2–dependent hematological cancers [1].

Targeting apoptosis is an attractive approach in cancer therapy. The BH3-only proteins of the BCL-2 family (having only the BCL-2 homology domain BH3) can trigger apoptosis by binding to the prosurvival members of this family and neutralizing their functional activity (sequestration of the proapoptotic Bcl-2 family members). The "BH3 mimetic" concept has prompted the development of small molecules capable of mimicking BH3-only proteins and thus inducing apoptosis. The prototype BH3 mimetic ABT-737 selectively targets the three prosurvival proteins BCL-XL, BCL-2, and BCL-W (but not MCL-1 or A1) and its oral derivative ABT-263 (navitoclax) has proved promising in clinical trials. However, their interaction with Bcl-xL provokes thrombocytopenia, which has proven to be the dose-limiting toxicity.  As a single agent, ABT-199 was as effective as ABT-737 in prolonging survival of immunocompetent tumor-bearing mice without causing thrombocytopenia. Both drugs acted rapidly but, contrary to prevailing models, their apoptotic activity did not rely upon the BH3-only protein Bim [2].

T-cell acute lymphoblastic leukemia (T-ALL) is a high-risk subtype of acute lymphoblastic leukemia (ALL) with gradually improved survival through introduction of intensified chemotherapy. However, therapy-resistant or refractory T-ALL remains a major clinical challenge. The T-ALL cell line LOUCY, which shows a transcriptional program related to immature T-ALL, exhibited high in vitro and in vivo sensitivity for ABT-199 in correspondence with high levels of BCL-2. In addition, ABT-199 showed synergistic therapeutic effects with different chemotherapeutic agents including doxorubicin, l-asparaginase, and dexamethasone. Furthermore, in vitro analysis of primary patient samples indicated that some immature, TLX3- or HOXA-positive primary T-ALLs are highly sensitive to BCL-2 inhibition, whereas TAL1 driven tumors mostly showed poor ABT-199 responses. Because BCL-2 shows high expression in early T-cell precursors and gradually decreases during normal T-cell differentiation, differences in ABT-199 sensitivity could partially be mediated by distinct stages of differentiation arrest between different molecular genetic subtypes of human T-ALL [3].

Researchers report that acute myeloid leukemia (AML) cell lines, primary patient samples, and murine primary xenografts are very sensitive to treatment with the selective BCL-2 antagonist ABT-199. In primary patient cells, the median IC50 was approximately 10 nmol/L, and cell death occurred within 2 hours. Ex vivo sensitivity results compare favorably with those observed for chronic lymphocytic leukemia, a disease for which ABT-199 has demonstrated consistent activity in clinical trials. Moreover, mitochondrial studies using BH3 profiling demonstrate activity at the mitochondrion that correlates well with cytotoxicity, supporting an on-target mitochondrial mechanism of action [4].

ABT-199 is under various clinical trials, being evaluated as single agent or in combination with other drugs for various cancers including AML, CLL etc [5-7].

1. Souers, A. J.; et. al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 2013, 19(2), 202-208.
2. Vandenberg, C. J.; et. al. ABT-199, a new Bcl-2-specific BH3 mimetic, has in vivo efficacy against aggressive Myc-driven mouse lymphomas without provoking thrombocytopenia. Blood 2013, 121(12), 2285-2288.
3. Peirs, S.; et. al. ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia. Blood 2014, 124(25), 3738-3747.
4. Pan, R.; et. al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov 2014, 4(3), 362-375.
5. An Extension Study of ABT-199 in Subjects With Advanced Non-Hodgkin's Lymphoma. NCT01969695 (retrieved on 24-04-2015)
6. A Phase 2 Study of ABT-199 in Subjects With Acute Myelogenous Leukemia (AML). NCT01994837 (retrieved on 24-04-2015)
7. A Study Evaluating ABT-199 in Combination With Low-Dose Cytarabine in Treatment-Na├»ve Subjects With Acute Myelogenous Leukemia (AML). NCT02287233 (retrieved on 24-04-2015)