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A drug engineered to "digest" extracellular RNA missed its primary endpoint in an early-stage clinical trial in systemic lupus erythematosus (SLE), though patients with higher disease activity scores did appear to show some improvement, researchers said.

Called RSLV-132, the product is a human RNase enzyme fused to an immunoglobulin fragment, explained a group led by James Posada, PhD, of Resolve Therapeutics in Miami. The idea is based on previous research indicating that circulating cell-free RNA provokes type I interferon release, which in turn helps drive SLE.

In a placebo-controlled phase IIa trial involving 64 lupus patients, those randomized to RSLV-132 showed only a weak trend toward greater improvement in Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) scores after 6 months, designated as the primary outcome measure (-6.2 vs -5.7 points with placebo), Posada and colleagues .

But among patients with relatively high disease activity scores at baseline, such as CLASI scores of 21 or more, rates of clinically important responses were substantially greater with the active drug.

SLE is among the most challenging autoimmune diseases, thanks to the wide range of manifestations and organ systems that may be involved. No one treatment approach is suitable for all patients; moreover, corticosteroids remain the long-term mainstay of therapy for many, which brings a range of adverse effects that often counterbalance relief of lupus symptoms. Thus, novel treatment approaches are always welcome.

The role of circulating RNA in lupus has been of interest for some time, Posada and colleagues explained. "Autoantibodies that bind to RNA-binding proteins have been extensively [characterized] and their [titers] carefully measured in clinical practice and clinical studies," they noted. Yet, they added, "surprisingly, little attention has been paid to the potent inflammatory properties of these antigens." Another aspect to this is that a "rapid detection and robust response to viral RNA" is a vital immune function; hence, the authors observed, the body "has evolved numerous, sensitive mechanisms to detect and respond to extracellular RNA, both foreign and self-derived." (In that vein, Resolve Therapeutics is now conducting a phase II trial with RSLV-132 .)

For the , the 64 adult patients were randomized 2:1 to RSLV-132 or placebo by infusion. To be eligible, participants needed to have a history of active SLE with moderate-severe skin involvement, including a CLASI score of at least 10. Participants also needed to test positive for at least one anti-RNA autoantibody.

Mean patient age was 45 and nearly all were women. CLASI scores averaged about 23 at baseline; scores on another standard system, the SLE Disease Activity Index 2000 version (SLEDAI-2K), averaged about 8.3.

When evaluating all patients, no significant difference was seen after 6 months between the active drug and placebo groups for change from baseline in either CLASI or SLEDAI-2K. In fact, the placebo group showed a slight trend toward greater improvement in SLEDAI scores and also for physician's global assessment. But in all cases, there was wide interindividual variability in these measures, with standard deviations of similar magnitude to the mean change from baseline.

The encouraging news was that patients with more severe baseline disease activity were more likely to meet standard criteria for clinical response at 6 months with RSLV-132. For example, for those with SLEDAI-2K scores of 9 or greater, 31% of patients given RSLV-132 achieved at least 50% improvement in CLASI score versus 11% on placebo; 62% versus 44% won the SLE Responder Index 4 classification; and 23% versus 11% achieved improvement in all British Isles Lupus Assessment Group A and B scores without showing worsening in other measures.

Safety findings also favored RSLV-132, with rates of treatment-emergent adverse events similar to or lower than in the placebo group.

Overall, Posada and colleagues concluded, "[t]he results warrant further larger studies in patients with active systemic disease as measured by SLEDAI score."

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