Use of the anti-apoptotic protein B-cell lymphoma 2 inhibitor venetoclax reduced total lymphocyte and disease-relevant B cells in women with systemic lupus erythematosus (SLE), according to recent research published in Lupus.
Peng Lu, MD, from AbbVie Inc. in Worcester, Massachusetts, and colleagues evaluated ascending single and multiple doses of oral venetoclax in women with SLE in a phase 1, double-blind randomized placebo-controlled study. Study participants received a single dose of 10, 30, 90, 180, 300, or 500 mg venetoclax, or 2 cycles of venetoclax at 30, 60, 120, 240, 400, or 600 mg for 1 week followed by 3 weeks off per cycle. The patients were between 18 and 65 years old and were diagnosed with SLE for at least 6 months. There were 48 patients in the single ascending dose (SAD) and 50 patients in the multiple ascending dose (MAD) groups; of these patients, 48 completed the SAD cycle and 44 completed the MAD cycle.
“SLE is a multiple-organ autoimmune disease whose pathogenesis includes polyclonal B-cell activation, the presence of multiple autoantibodies, including autoantibodies against angiotensin II and endothelin receptors that may be involved in vasculopathies associated with SLE and other autoimmune diseases, dysregulation of follicular helper T cells, and upregulation of type-1 interferon signature genes,” Dr Lu and colleagues wrote. “Because of this complexity, therapeutic agents that affect multiple pathways, such as venetoclax, are expected to emerge as viable options for disease management.”
Patients in the SAD group saw significant depletion in total lymphocytes, B cells, and T cells at the 500-mg dose and significant depletions of B cells at the 300-mg dose. In the MAD groups, there were significant depletions after 7 days in total lymphocytes, B cells, and T cells, with B cells showing significant depletion in the first cycle at the 200-, 400-, and 600-mg doses. In both SAD and MAD groups, Dr Lu and colleagues found B cells depleted significantly faster than total lymphocytes or T cells.
Although the researchers noted no significant adverse events in the venetoclax groups, the adverse event rate was slightly higher compared with the placebo groups; the most common adverse events reported were nausea, headache, and fatigue.
Summary and Clinical Applicability
Venetoclax treatment may contribute to the depletion of naive and memory B cells in women with SLE.
“The naive B-cell repertoire in patients with SLE is enriched in autoreactive B cells that have escaped normal deletion mechanisms during development, and autoreactive memory B cells have probably undergone affinity maturation in a germinal center to produce high-affinity pathogenic autoantibodies,” Dr Lu and colleagues wrote. “Our data indicate that naive and switched memory B cells are equally sensitive to venetoclax. Moreover, several memory B-cell populations that are expanded in patients with SLE are sensitive to venetoclax.”
Limitations and Disclosures
Researchers noted the lack of long-term data on how venetoclax depletes T cells, lack of data on the effect of venetoclax in men based on animal studies, and lack of data on the efficacy of venetoclax in patients with active SLE as limitations in this study.
The study investigators report affiliations with AbbVie, which manufactures venetoclax.
Lu P, Fleischmann R, Curtis C, et al. Safety and pharmacodynamics of venetoclax (ABT-199) in a randomized single and multiple ascending dose study in women with systemic lupus erythematosus [published online January 1, 2017]. Lupus. doi: 10.1177/0961203317719334