abt-199 and Lupus-Erythematosus--Systemic

Venetoclax is a selective inhibitor of B-cell lymphoma-2, which plays a role in the development of various autoimmune diseases including systemic lupus erythematosus. The aim of these analyses was to quantify the exposure-response relationship for venetoclax effects on B-lymphocyte and total lymphocyte counts as pharmacodynamic markers of efficacy and safety, respectively, in women with systemic lupus erythematosus. The developed modeling framework was also used to evaluate venetoclax effects following cyclic, continuous, or induction/maintenance dosing paradigms as potential dosing alternatives in systemic lupus erythematosus.. Serial pharmacokinetic and lymphocyte count data from 73 women enrolled in a phase I study of venetoclax (single doses of 10-500 mg or two cycles of 30-600 mg or placebo once daily for 7 days followed by a 21-day washout) were analyzed using a sequential population pharmacokinetic/pharmacodynamic modeling approach. Simulations to evaluate changes in B-lymphocyte and total lymphocyte counts following different venetoclax dosing scenarios were conducted.. Venetoclax treatment in women with systemic lupus erythematosus was associated with exposure-dependent reductions in B lymphocytes, and to a lesser extent, total lymphocyte counts. Results from this study support evaluation of B-cell lymphoma-2 inhibitors as potential therapies for the treatment of systemic lupus erythematosus. CLINICALTRIALS.GOV: NCT01686555.

Topics: Adult; Aged; Antineoplastic Agents; Autoimmune Diseases; B-Lymphocytes; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Female; Humans; Lupus Erythematosus, Systemic; Lymphocyte Count; Middle Aged; Models, Theoretical; Placebos; Proto-Oncogene Proteins c-bcl-2; Safety; Sulfonamides; Treatment Outcome

Objective The anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) may contribute to the pathogenesis of systemic lupus erythematosus. The safety, tolerability, and pharmacodynamics of the selective Bcl-2 inhibitor venetoclax (ABT-199) were assessed in women with systemic lupus erythematosus. Methods A phase 1, double-blind, randomized, placebo controlled study evaluated single ascending doses (10, 30, 90, 180, 300, and 500 mg) and multiple ascending doses (2 cycles; 30, 60, 120, 240, 400, and 600 mg for 1 week, and then 3 weeks off per cycle) of orally administered venetoclax. Eligible participants were aged 18-65 years with a diagnosis of systemic lupus erythematosus for 6 months or more receiving stable therapy for systemic lupus erythematosus (which could have included corticosteroids and/or stable antimalarials). Results All patients (48/48) completed the single ascending dose, 25 continued into the multiple ascending dose, and 44/50 completed the multiple ascending dose; two of the withdrawals (venetoclax 60 mg and 600 mg cohorts) were due to adverse events. Adverse event incidences were slightly higher in the venetoclax groups compared with the placebo groups, with no dose dependence. There were no serious adverse events with venetoclax. The most common adverse events were headache, nausea, and fatigue. Venetoclax 600 mg multiple ascending dose treatment depleted total lymphocytes and B cells by approximately 50% and 80%, respectively. Naive, switched memory, and memory B-cell subsets enriched in autoreactive B cells exhibited dose-dependent reduction of up to approximately 80%. There were no consistent or marked changes in neutrophils, natural killer cells, hemoglobin, or platelets. Conclusions Venetoclax was generally well tolerated in women with systemic lupus erythematosus and reduced total lymphocytes and disease-relevant subsets of antigen-experienced B cells. Registration ClinicalTrials.gov: NCT01686555.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antibodies, Antinuclear; Antineoplastic Agents; B-Lymphocyte Subsets; B-Lymphocytes; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Lupus Erythematosus, Systemic; Middle Aged; Sulfonamides; Treatment Outcome; Young Adult

Venetoclax is an oral selective Bcl-2 inhibitor approved for the treatment of patients with chronic lymphocytic leukemia with 17p deletion. Mechanistic and preclinical evidence warranted evaluation of venetoclax for the treatment of systemic lupus erythematosus (SLE). This work characterized the pharmacokinetics of venetoclax in female subjects with SLE.. Single (10-500 mg) and multiple (30-600 mg) escalating doses of venetoclax or matching placebo were evaluated using randomized, double-blind, placebo-controlled designs (6 active and 2 placebo per dose with 73 unique SLE patients enrolled, 25 of whom enrolled twice). The multiple-dose evaluation consisted of two cycles, each with once-daily dosing for 7 days followed by a 21-day washout. Non-compartmental and population pharmacokinetic analyses of venetoclax serial plasma concentrations were conducted.. Venetoclax exhibited approximately dose-proportional exposures, with peak concentrations observed 4-8 h post-dose. Venetoclax steady-state exposures were achieved by day 4 of dosing, and the median area under the plasma concentration-time curve (AUC) accumulation ratio ranged from 1.1 to 1.5. A two-compartment model with first-order absorption and elimination described venetoclax pharmacokinetics. The estimates (95% bootstrap confidence interval) for venetoclax apparent clearance, central and peripheral volumes of distribution, intercompartmental clearance, absorption rate constant, and lag time were 16.3 L/h (14.6-17.9), 37 L (26-57), 122 L (98-183), 3.7 L/h (2.6-5.0), 0.13 h. In female subjects with SLE, venetoclax displayed pharmacokinetic characteristics consistent with previous observations in subjects with hematologic malignancies. CLINICALTRIALS.. NCT01686555.

Topics: Adult; Area Under Curve; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Humans; Lupus Erythematosus, Systemic; Models, Biological; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Treatment Outcome

Bruton's tyrosine kinase (BTK) is a Tec family kinase that plays an essential role in B-cell receptor (BCR) signaling as well as Fcγ receptor signaling in leukocytes. Pharmacological inhibition of BTK has been shown to be effective in treating hematological malignancies and is hypothesized to provide an effective strategy for the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. We report the discovery and preclinical properties of JNJ-64264681 (

Topics: Agammaglobulinaemia Tyrosine Kinase; Arthritis, Rheumatoid; Autoimmune Diseases; Humans; Lupus Erythematosus, Systemic; Protein Kinase Inhibitors

Interferon-α (IFNα)-producing plasmacytoid dendritic cells (PDCs) are implicated in the pathogenesis of systemic lupus erythematosus (SLE). IFNα-related genes are highlighted among SLE susceptibility alleles and are characteristically expressed in the blood of patients with SLE, while in mouse models of lupus, PDC numbers and IFNα production are increased. This study was undertaken to investigate the effects of inhibitors that selectively target different antiapoptotic molecules on the survival of PDCs.. PDC numbers, in vitro survival, and expression of antiapoptotic molecules were evaluated in lupus-prone (NZB × NZW)F1 (NZB/NZW) mice. The impact of Bcl-2 antagonists and glucocorticoids on PDCs was evaluated in vitro and in vivo. IFNα production by NZB/NZW mice was evaluated before and after treatment with Bcl-2 antagonists.. PDCs, but not lymphoid tissue-resident conventional DCs, largely relied on the antiapoptotic protein Bcl-2 for survival. The enlarged PDC compartment in NZB/NZW mice was associated with selectively prolonged survival and increased Bcl-2 transcription. Functionally, this resulted in enhanced production of IFNα. Bcl-2 inhibitors selectively killed mouse and human PDCs, including PDCs from SLE patients, but not conventional DCs, dampened IFNα production by PDCs, and synergized with glucocorticoids to kill activated PDCs.. Enhanced PDC survival is a likely contributing factor to enhanced IFNα production by lupus PDCs. Bcl-2 antagonists potently and selectively kill PDCs and reduce IFNα production. Thus, we believe that they are attractive candidates for treating PDC-associated diseases.

Topics: Animals; Annexin A5; Antibodies, Antinuclear; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Survival; Cells, Cultured; Dendritic Cells; Flow Cytometry; Glucocorticoids; Humans; Interferon-alpha; Lupus Erythematosus, Systemic; Mice; Mice, Inbred C57BL; Mice, Inbred NZB; Mice, Transgenic; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Real-Time Polymerase Chain Reaction; Sulfonamides