Background B-cell Lymphoma 2 (Bcl-2) is an anti-apoptotic protein that plays a critical role in hemostasis of auto reactive lymphocytes (B and T cells) thought to be involved in various autoimmune diseases such as SLE. Abnormalities in the Bcl-2 mediated lymphocyte apoptotic process have been implicated in development of these autoimmune diseases. Venetoclax is an orally bioavailable, selective Bcl-2 inhibitor currently under evaluation for treatment of SLE and several oncology indications.

Objectives The objective of this work was to quantitatively characterize the relationship between venetoclax plasma concentrations and time course of the reduction in B and total lymphocyte counts following single and multiple dosing of venetoclax in female subjects with SLE

Methods Serial pharmacokinetic and lymphocyte count data from a double-blind, randomized, placebo-controlled Phase 1 study of venetoclax (single doses of 10, 30, 90, 180, 300 and 500 mg or two cycles of 30, 60, 120, 240, 400 and 600 mg or matching placebo once daily for seven days followed by 21 day washout) in female subjects with SLE (N=98) were analyzed using non-linear mixed-effects modeling.

Results Venetoclax plasma concentrations in subjects with SLE were characterized using a two-compartment pharmacokinetic model with first-order elimination. Venetoclax resulted in reduction of B and total lymphocytes and the effect was consistent between the two cycles of treatment for the multiple dose evaluation. An indirect response model with venetoclax stimulating B lymphocytes turnover was utilized to describe venetoclax exposure/ B lymphocytes relationship. The slope for stimulation of the first order rate constant of B lymphocytes turnover was estimated at 0.02 [95% CI: 0.01, 0.03] day^–1/(ng/mL) following multiple dosing. An E_max model with an effect site (to introduce time-delay) was used to describe venetoclax effect on total lymphocytes. The maximum effect was estimated to be 60% relative to baseline with an estimated EC₅₀ of 225 [95% CI: 146 to 383] ng/mL. Baseline B and total lymphocytes were identified as covariates for venetoclax slope and EC₅₀, respectively. For the cyclic regimens of 120 and 600 mg, the model predicted typical reduction from baseline at day 7 of 26% and 77%, respectively, for B lymphocyte (for a baseline value of 0.18x10⁹ cells/L) and 15% and 37%, respectively, for total lymphocytes (for a baseline value of 1.7x10⁹ cells/L)

Conclusions The current analyses demonstrate that B lymphocytes are more sensitive than total lymphocytes to the effects of venetoclax and these effects were quantitatively characterized in female subjects with SLE using an exposure-response modeling approach. The developed models will be utilized to guide the design of future trials of Bcl-2 inhibitors in subjects with SLE, including dose selection and assessment of cyclic versus continuous dosing.

Disclosure of Interest M. Minocha Shareholder of: AbbVie, Employee of: AbbVie, A. Jones Shareholder of: AbbVie, Employee of: AbbVie, P. Lu Shareholder of: AbbVie, Employee of: AbbVie, A. Othman Shareholder of: AbbVie, Employee of: AbbVie