Background/Purpose:

BDCA2 is a plasmacytoid dendritic cell (pDC)-specific receptor that, upon activation, inhibits the production of inflammatory factors by human pDCs, including IFN-α a major player in the pathogenesis of SLE. This 3-Part Phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical efficacy of single and multiple ascending doses (SAD-MAD) of BIIB059 in HV and SLE subjects (NCT02106897. Comparison of PK and PD parameters between HV and SLE as well as final PK-PD results from the SAD in SLE and MAD results are presented.

Methods:

In the SAD part, 12 subjects with active SLE were randomized 2:1 to receive a single IV dose level of BIIB059 (20mg/kg) or placebo. In the MAD part, HV received either 2 (Cohort 9 to 11) or 3 (Cohort 12) SC administrations of Placebo or BIIB059 20, 50 or 150mg (Cohort: 9 , 10, 11) Q4W or 3 SC 300mg (Cohort 12) Q2W. Subjects with active SLE , received either 2 (Cohort 13) or 3 (Cohort 14) SC placebo or BIIB059 50 mg (Cohort 13) or 300 mg (Cohort 14). The dose levels were selected based on emerging data from the Part 1 in HV and was not to exceed the maximum tolerated dose or the highest evaluated and tolerable dose. Blood samples were obtained before and after each dose administration to characterize PK and PD (BDCA2 on pDC) relationship for BIIB059.

Results:

Part 1 PK and PD results (SAD) in healthy volunteers, HV) and Part 2 PD results have been previously presented (single dose in SLE)^1-2 . In Part 2 of the study, following IV administration, mean t_1/2 in SLE subjects was 18.1 days, with a mean CL of 0.251 L/day and a mean volume of distribution V_ss of 5.41 L. Following SC administration, in Part 3a, mean t_1/2 in HV subjects ranged from 13.3 to 19.5 days, mean CL_ss/F ranged from 0.28 to 0.367 L/day and V_z/F ranged from 7.23 to 9.36 L. In Part 3b, mean t_1/2 in SLE subjects ranged from 12.6 to 20.5 days with a mean CL_ss/F of 0.455 to 0.485 L/day and a mean V_z/F of 5.93 and 12.8 L. Exposure (AUC and Cmax) for BIIB059 increased with dose in both HV and SLE subjects. However exposure in SLE subjects was approximately 40% lower compared to HV which could not be attributed to body weight. The observed mean accumulation ratio for AUC was slightly lower in SLE subjects (2.58) compared to HV (2.66) after BIIB059 SC administration. Complete BDCA2 internalization was achieved at all dose levels, the duration of which was dose dependent, and was similar for HV and SLE subjects. Reappearance of BDCA2 on circulating pDCs occurred when serum concentrations of BIIB059 dropped to ~1 μg/mL. BIIB059 was generally well tolerated; the incidence of adverse events (AEs) was similar between BIIB059- and placebo-treated HV and/or SLE subjects in both SAD and MAD.

Conclusion:

BIIB059 was well tolerated with an acceptable safety profile.

Exposure in SLE subjects was lower compared to HV while BDCA2 internalization was similar. Based on the Phase 1 data, BIIB059 is currently evaluated in a Phase 2 trial (NCT02847598).

References:

1 Martin D et al. Poster 774. Arthritis Rheumatol. 2016; 68 (suppl10).

2 Furie R et al. Abstract 2013. Arthritis Rheumatol. 2016; 68 (suppl 10).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/safety-tolerability-pharmacokinetic-and-pharmacodynamic-effects-of-biib059-a-monoclonal-antibody-targeting-bdca2-following-administration-of-intravenous-and-subcutaneous-sin/