ABSTRACT
OBJECTIVE: We undertook this study to explore the efficacy, safety, and tolerability of ziritaxestat, a selective autotaxin inhibitor, in patients with early diffuse cutaneous systemic sclerosis (dcSSc). METHODS: NOVESA was a 24-week, multicenter, phase IIa, double-blind, placebo-controlled study. Adults with dcSSc were randomized to oral ziritaxestat 600 mg once daily or matching placebo. The primary efficacy end point was change from baseline in modified Rodnan skin score (MRSS) at week 24. Secondary end points assessed safety and tolerability; other end points included assessment of skin and blood biomarkers. Patients in NOVESA could enter a 104-week open-label extension (OLE). RESULTS: Patients were randomized to ziritaxestat (n = 21) or placebo (n = 12). Reduction in MRSS was significantly greater in the ziritaxestat group versus the placebo group (-8.9 versus -6.0 units, respectively; P = 0.0411). Placebo patients switching to ziritaxestat in the OLE showed similar reductions in MRSS to those observed for ziritaxestat patients in the parent study. Ziritaxestat was well tolerated; the most frequent treatment-related treatment-emergent adverse events were headache and diarrhea. Circulating lysophosphatidic acid (LPA) C18:2 was significantly reduced, demonstrating ziritaxestat target engagement, and levels of fibrosis biomarkers were reduced in the blood. No differentially expressed genes were identified in skin biopsies. Significant changes in 109 genes were identified in blood samples. CONCLUSION: Ziritaxestat resulted in significantly greater reduction in MRSS at week 24 than placebo; no new safety signals emerged. Biomarker analysis suggests ziritaxestat may reduce fibrosis. Modulation of the autotaxin/LPA pathway could improve skin involvement in patients with dcSSc. A plain language summary is provided in the Supplementary Material, available on the Arthritis & Rheumatology website at https://onlinelibrary.wiley.com/doi/10.1002/art.42477.
Subject(s)
Scleroderma, Diffuse , Adult , Humans , Scleroderma, Diffuse/pathology , Treatment Outcome , Skin/pathology , Biopsy , Double-Blind Method , FibrosisABSTRACT
BACKGROUND: Platelet (PLT) support is critical to the care of patients with thrombocytopenia, but allogeneic transfusions carry risk. Pathogen reduction mitigates some transfusion risks, but effects on PLT function remain a concern. This clinical pilot study assessed the effect of pathogen reduction technology with riboflavin plus ultraviolet light using thrombelastography (TEG). STUDY DESIGN AND METHODS: This prospective, randomized, crossover study compared Mirasol-treated (MIR) and standard reference (REF) PLT transfusions. PLT counts and TEG measurements were taken at pretransfusion and 1- and 24-hour-posttransfusion time points. The primary outcome measure was the pretransfusion to 1-hour-posttransfusion change in maximum amplitude (ΔMA(1 hr)). Secondary endpoints included ΔMA among other time points, relative MA, and the PLT count-MA correlation. RESULTS: Of 16 enrolled patients, one withdrew before study treatment and three did not require two transfusions, leaving 12 patients in the efficacy analyses (seven MIR-REF, five REF-MIR). ΔMA(1 hr) (mean ± SD) was 10.60 ± 6.47 mm for MIR and 14.33 ± 5.38 mm for REF (p = 0.20, n = 10). ΔMA(24hr) was 9.49 ± 7.94 for MIR and 7.13 ± 3.08 for REF (p = 0.38, n = 9); ΔMA(24hr-1 hr) was -1.11 ± 2.95 for MIR and -7.20 ± 4.81 for REF (p = 0.016, n = 8). MA values for MIR and REF correlated with the log of PLT count (rMIR = 0.6901, rREF = 0.7399). CONCLUSION: TEG is sensitive to changes in hemostatic function resulting from a single PLT transfusion. MIR and REF provided similar increments in hemostatic function in the immediate posttransfusion period and at 24 hours. A significant difference detected for ΔMA(24hr-1 hr) suggests different PLT clearance mechanisms. The relationship of these variables to clinically meaningful outcomes, for example, bleeding events or transfusion requirements, has yet to be determined.