Background/Purpose: Plasmacytoid dendritic cells (pDCs) secrete large amounts of type I interferon (IFN) and other cytokines upon activation. pDCs migrate to sites of active disease in lupus. VIB7734 is a monoclonal antibody that selectively targets pDCs for antibody-dependent cellular cytolysis.

Methods: VIB7734 was tested in a phase 1, randomized, double-blind, placebo-controlled, multiple ascending dose clinical trial (NCT03817424). Adult subjects were enrolled in 3 sequential cohorts and received placebo (n=9) or 5 mg (n=6, cohort 1), 50 mg (n=8, cohort 2), or 150 mg (n=8, cohort 3) of VIB7734. Cohort 1 enrolled subjects with SLE or Sjogren’s syndrome with no minimum disease activity requirement. Cohorts 2 & 3 included subjects with SLE or cutaneous lupus erythematosus (CLE) with a CLE Disease Area and Severity Index Activity score (CLASI-A) of ≥ 8. Subjects received VIB7734 or placebo subcutaneously every 4 weeks for 3 doses as an add-on to standard of care. In cohorts 2 and 3, a biopsy of affected skin was performed at baseline and Month 3. pDC levels were quantified in the blood and skin. The type I IFN signature was measured in blood. As a marker of IFN activity, myxovirus resistance protein A (MxA) was quantified within the epidermis as the percent of area reaching the positive staining threshold.

Results: 31 subjects were randomized and treated; all completed the study. Reductions in circulating pDCs were evident at Week 1 and persisted through the 3-month treatment period (Figure 1). A high type I IFN signature was present at baseline in 18 of 23 subjects (78%) in cohorts 2 and 3. The median change in IFN signature at Month 3 was -54% in the VIB7734 50 mg group, -83% in the VIB7734 150 mg group, and +8% in the placebo group. On the Month 3 biopsy the median change in pDC density was -87% for the 50 mg group, -99% for the 150 mg group, and -14% for the placebo group. The median area of MxA staining decreased with VIB7734 treatment (50 mg group: 50% to 1.7% affected area; 150 mg group: 90% to 1.1% affected area; placebo group: 5.5% to 18% affected area). The median change in CLASI-A from baseline to Month 3 was -5 in the 50 mg group, -9.5 in the 150 mg group, and -5 in the placebo group (Figure 2).  At Month 3, a ≥50% improvement in CLASI-A was observed in 9 of 16 (56%) VIB7734-treated subjects and 2 of 7 (29%) placebo-treated subjects. No serious adverse events occurred in VIB7734-treated subjects. The proportion of subjects with an adverse event was similar in the VIB7734 and placebo groups (73% vs. 67%).

Conclusion: VIB7734 reduced blood and skin pDCs, thereby reducing type I IFN levels in blood and inflamed skin. More CLE subjects treated with VIB7734 than placebo had a clinically significant improvement in CLASI-A scores, and VIB7734 had an acceptable safety profile. Additional studies of VIB7734 in lupus are planned.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/targeting-plasmacytoid-dendritic-cells-improves-cutaneous-lupus-erythematosus-skin-lesions-and-reduces-type-i-interferon-levels-results-of-a-phase-1-study-of-vib7734/