Background/Purpose: Very late antigen-1 (VLA-1; α1β1 integrin), a cell adhesion molecule expressed on activated lymphocytes and monocytes/macrophages, binds extracellular matrix molecules and facilitates migration, proliferation, and retention of these cells at sites of inflammation. Inhibition of VLA-1 by antibody blockade or genetic ablation is associated with decreased disease severity in animal models of acute and chronic inflammation, including models of rheumatoid arthritis (RA). This Phase 1, escalating single-dose study evaluated safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of intravenous (IV) and subcutaneous (SC) administration of SAN-300, an anti-VLA-1 antibody, in healthy subjects and patients with active RA.

Methods:  In a randomized, placebo-controlled design, 66 healthy subjects received single IV or SC SAN-300 administrations (0.03-2.0 mg/kg IV; 2.0-6.0 mg/kg SC; N=45) or placebo (N=21). Two patients with active RA received SAN-300 2.0 mg/kg IV (N=1) or placebo (N=1). Serum SAN-300 concentrations, VLA-1 receptor occupancy (RO), and safety were assessed through Day 29. American College of Rheumatology (ACR) response criteria and Disease Activity Score 28 based on CRP (DAS28-CRP) were assessed in patients with active RA.

Results: Serum SAN-300 concentrations were undetectable in most subjects at low doses (0.03-0.3 mg/kg IV). In subjects receiving SAN-300 0.6-2.0 mg/kg IV or 2.0-6.0 mg/kg SC, a nonlinear pharmacokinetic profile was observed. Essentially complete VLA-1 RO (≥ 90%) was noted at doses above 0.8 mg/kg IV and 2.0 mg/kg SC, with durable RO (> 50%) observed through Day 8 for SAN-300 2.0 mg/kg SC and Day 15 for SAN-300 4.0-6.0 mg/kg SC. SAN-300 was generally well tolerated. No severe/serious infections were reported. Most adverse events (AEs) were mild or moderate in intensity. The most common AEs upon IV administration were mild or moderate headaches and infusion reactions. Infusion reactions occurred with 0.8-2.0 mg/kg IV; all events improved by 72 h. Among subjects receiving SAN-300 SC, headaches and mild injection-site reactions were most common. Transient, mild to moderate decreases in absolute neutrophil counts (1.1-1.9 x 10⁹/L; normal: 1.9-8.0 x 10⁹/L) were observed, mostly at higher doses. All cases resolved without sequelae. The single patient with active RA who received SAN-300 2.0 mg/kg IV met ACR50 at Days 15 and 29 and achieved a good response per EULAR criteria based on DAS28-CRP at Day 15 (‑1.66; absolute score 2.31), and a moderate response at Day 29 (-0.92; 3.05). The placebo patient did not meet criteria for ACR20 or DAS28-CRP response at any time point.

Conclusion: In this first-in-human study, SAN-300, an antibody against novel therapeutic target VLA-1, showed nonlinear pharmacokinetics. However, durable saturation of VLA-1 was observed following IV or SC administration. SAN-300 was generally well tolerated, with the SC formulation mitigating the occurrence of mild or moderate infusion reactions seen at higher IV doses. Given favorable tolerability, encouraging RO, and ease of administration, the SC route of administration warrants investigation in future multiple-dose studies in patients with active RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/safety-pharmacokinetics-and-pharmacodynamics-of-san-300-a-novel-monoclonal-antibody-against-very-late-antigen-1-results-of-a-phase-1-study-in-healthy-volunteers-and-patients-with-active-rheumatoid/