Abstract
Background
Primary Sjögren syndrome (pSjS) is a chronic autoimmune disorder characterized by mucosal dryness and systemic symptoms. We tested the effects of inhibition of cathepsin S using the potent and selective inhibitor RO5459072 on disease activity and symptoms of pSjS.
Methods
This was a randomized, double-blind, placebo-controlled, parallel-group, Phase IIA study to investigate the effects of RO5459072 (100 mg twice daily [BID]; 200 mg per day). Seventy-five patients with pSjS were randomized 1:1 to receive either RO5459072 or placebo for 12 weeks. The primary outcome was the proportion of patients with a ≥3 point reduction from baseline in European League against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) score. We also investigated the effects of RO5459072 on quality of life, exocrine gland function, biomarkers related to Sjögren’s syndrome, and safety and tolerability.
Results
The proportion of patients showing an improvement in ESSDAI score was not significantly different between the RO5459072 and placebo arms. No clinically meaningful treatment effects were observed in favor of RO5459072 for all secondary outcomes. Analysis of soluble biomarkers indicated target engagement between RO5459072 and cathepsin S. There were modest decreases in the number of circulating B-cells and T-cells in the RO5459072 group, although these did not reach significance. RO5459072 was safe and well-tolerated.
Conclusions
There was no clinically relevant improvement in ESSDAI score (primary endpoint), and no apparent benefit in favor of RO5459072 in any of the secondary endpoints. Further work is needed in order to understand the mechanisms of MHC-II-mediated immune stimulation in pSjS.
Primary Sjögren syndrome (pSjS) is a chronic autoimmune disorder characterized by mucosal dryness and systemic symptoms. We tested the effects of inhibition of cathepsin S using the potent and selective inhibitor RO5459072 on disease activity and symptoms of pSjS.
Methods
This was a randomized, double-blind, placebo-controlled, parallel-group, Phase IIA study to investigate the effects of RO5459072 (100 mg twice daily [BID]; 200 mg per day). Seventy-five patients with pSjS were randomized 1:1 to receive either RO5459072 or placebo for 12 weeks. The primary outcome was the proportion of patients with a ≥3 point reduction from baseline in European League against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) score. We also investigated the effects of RO5459072 on quality of life, exocrine gland function, biomarkers related to Sjögren’s syndrome, and safety and tolerability.
Results
The proportion of patients showing an improvement in ESSDAI score was not significantly different between the RO5459072 and placebo arms. No clinically meaningful treatment effects were observed in favor of RO5459072 for all secondary outcomes. Analysis of soluble biomarkers indicated target engagement between RO5459072 and cathepsin S. There were modest decreases in the number of circulating B-cells and T-cells in the RO5459072 group, although these did not reach significance. RO5459072 was safe and well-tolerated.
Conclusions
There was no clinically relevant improvement in ESSDAI score (primary endpoint), and no apparent benefit in favor of RO5459072 in any of the secondary endpoints. Further work is needed in order to understand the mechanisms of MHC-II-mediated immune stimulation in pSjS.
| Original language | English |
|---|---|
| Journal | Rheumatology (Oxford) |
| Early online date | 2 Mar 2023 |
| DOIs | |
| Publication status | E-pub ahead of print - 2 Mar 2023 |
Keywords
- Sjogren's Syndrome
- cathepsin
- Clinical trial