Atacicept, a BLyS-specific inhibitor and APRIL blocker, is a TACI-Fc fusion glycoprotein that binds B cell activating factor (BAFF) and APRIL with dissociation constants (Kd) of 106 pM and 33 pM, respectively, and reduces BAFF- and APRIL-mediated signaling. BAFF is also known as BlyS.
Reduction in BAFF- and APRIL-mediated signaling decreases production of serum galactose-deficient IgA1 (Gd-IgA1), which is implicated in the pathophysiology of IgAN.
In IgAN patients treated with atacicept once weekly in the Origin 3 study, serum Gd-IgA1, Immunoglobulin A (IgA), Immunoglobulin G (IgG), and Immunoglobulin M (IgM) levels decreased within 4 weeks and these reductions were sustained through Week 36. By Week 36, mean serum levels were reduced from baseline by 68% for Gd-IgA1, 64% for IgA, 36% for IgG, and 75% for IgM.
Following once weekly SC administration of atacicept 150 mg in IgAN patients, atacicept pharmacokinetics increased proportionally over a dose range of 75 to 150 mg. Steady state was achieved after approximately 24 weeks. Following the first SC dose, the maximum atacicept concentrations were reached approximately 36 hours after atacicept administration.
Central and peripheral volume of distribution were 44 L and 61 L, respectively, in patients with IgAN.
No drug metabolism studies have been conducted. Atacicept is a therapeutic protein that is expected to be catabolized into small peptides and amino acids by general catabolic degradation processes in multiple tissues.
The estimated clearance of atacicept is 3.2 L/day, and the elimination half-life is approximately 40 days in IgAN patients.
No clinically significant differences in the pharmacokinetics of atacicept were observed based on sex, age (18 to 74 years), weight (38.4 to 138 kg), race, and mild to severe renal impairment (eGFR: 22 to 89 mL/min).
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