A 24-Week, Phase IIa, Randomized, Double-Blind, Placebo-Controlled Study of Ziritaxestat in Early Diffuse Cutaneous...

Area of Science:

• Rheumatology
• Immunology
• Pharmacology

Background:

• Diffuse cutaneous systemic sclerosis (dcSSc) is a severe autoimmune condition characterized by skin fibrosis.
• Current treatments for dcSSc have limited efficacy and significant side effects.
• The autotaxin (ATX)/lysophosphatidic acid (LPA) pathway is implicated in fibrotic processes.

Purpose of the Study:

• To evaluate the efficacy, safety, and tolerability of ziritaxestat, a selective ATX inhibitor, in patients with early dcSSc.
• To assess the impact of ziritaxestat on skin fibrosis and relevant biomarkers.
• To explore the potential of targeting the ATX/LPA pathway for dcSSc treatment.

Main Methods:

• The NOVESA study was a 24-week, multicenter, double-blind, placebo-controlled, Phase IIa trial.
• Adult patients with early dcSSc were randomized to receive oral ziritaxestat (600 mg daily) or placebo.
• The primary endpoint was the change in modified Rodnan skin score (MRSS) at week 24; secondary endpoints included safety, tolerability, and biomarker analysis.

Main Results:

• Ziritaxestat demonstrated a significantly greater reduction in MRSS compared to placebo (-8.9 vs. -6.0 units, P=0.0411).
• Ziritaxestat was well-tolerated, with headache and diarrhea as the most frequent adverse events.
• Treatment led to a significant reduction in circulating lysophosphatidic acid (LPA) C18:2, indicating target engagement, and decreased fibrosis biomarkers.

Conclusions:

• Ziritaxestat significantly improved skin involvement in dcSSc patients compared to placebo.
• The drug was well-tolerated, and biomarker data suggest a potential anti-fibrotic effect.
• Modulating the autotaxin/LPA pathway with ziritaxestat may offer a novel therapeutic strategy for dcSSc.