Serum ARGS-aggrecan in a phase 2 clinical trial targeting osteoarthritis
Larsson, Staffan LU
; Lalande, Agnes
; Lohmander, L Stefan
LU
; Soret, Perrine
; Bernard, Katy
; Pueyo, Maria
and Struglics, André
LU
(2024)
In Osteoarthritis and Cartilage
p.1-8
- Abstract
- To monitor serum concentrations of the aggrecan alanine-arginine-glycine-serine (ARGS) neoepitope in a clinical trial of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5 inhibition as disease-modifying therapy of knee osteoarthritis, and to investigate relationships between reduction in ARGS and change in cartilage thickness, knee-related pain and function.
Design
ROCCELLA trial participants received once-daily oral S201086 75, 150 or 300 mg, or placebo, for 52 weeks. Serum was collected at baseline, 4, 12, 28 and 52 weeks, and 2 weeks post-treatment with ARGS measured by an in-house immunoassay. Change from baseline to week 52 in central medial femorotibial compartment cartilage thickness was measured... (More) - To monitor serum concentrations of the aggrecan alanine-arginine-glycine-serine (ARGS) neoepitope in a clinical trial of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5 inhibition as disease-modifying therapy of knee osteoarthritis, and to investigate relationships between reduction in ARGS and change in cartilage thickness, knee-related pain and function.
Design
ROCCELLA trial participants received once-daily oral S201086 75, 150 or 300 mg, or placebo, for 52 weeks. Serum was collected at baseline, 4, 12, 28 and 52 weeks, and 2 weeks post-treatment with ARGS measured by an in-house immunoassay. Change from baseline to week 52 in central medial femorotibial compartment cartilage thickness was measured by magnetic resonance imaging, function and pain by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscores. Associations between cumulative change in ARGS and change in cartilage thickness or WOMAC subscores were evaluated by linear regression.
Results
S201086 reduced serum levels of ARGS in a dose-dependent manner throughout the treatment period. Maximal reduction was at 4 weeks with a 58.5% [95% CI 60.8%, 56.2%] reduction of ARGS compared to baseline for 300 mg S201086. Two weeks post-treatment, ARGS concentrations rebounded with a dose-dependent overshoot compared to baseline levels. Cumulative change of ARGS concentration from baseline to week 52 had no effect on change in cartilage thickness (slope −0.8×10−6 [−2.9×10−6, 1.3×10−6]) or change in WOMAC pain and function (slopes −30×10−6 [−64×10−6, 5.2×10−6] and −97×10−6 [−214×10−6, 20×10−6], respectively) at week 52.
Conclusion
Systemic inhibition of ADAMTS-5 resulted in markedly reduced serum ARGS, but change in serum ARGS concentrations showed no association with the progression of cartilage thinning, or patient reported pain and function. (Less) - Abstract (Swedish)
- OBJECTIVE: To monitor serum concentrations of the aggrecan alanine-arginine-glycine-serine (ARGS) neoepitope in a clinical trial of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5 inhibition as disease-modifying therapy of knee osteoarthritis, and to investigate relationships between reduction in ARGS and change in cartilage thickness, knee-related pain and function. DESIGN: ROCCELLA trial participants received once-daily oral S201086 75, 150 or 300 mg, or placebo, for 52 weeks. Serum was collected at baseline, 4, 12, 28 and 52 weeks, and 2 weeks post-treatment with ARGS measured by an in-house immunoassay. Change from baseline to week 52 in central medial femorotibial compartment cartilage thickness was measured... (More)
- OBJECTIVE: To monitor serum concentrations of the aggrecan alanine-arginine-glycine-serine (ARGS) neoepitope in a clinical trial of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5 inhibition as disease-modifying therapy of knee osteoarthritis, and to investigate relationships between reduction in ARGS and change in cartilage thickness, knee-related pain and function. DESIGN: ROCCELLA trial participants received once-daily oral S201086 75, 150 or 300 mg, or placebo, for 52 weeks. Serum was collected at baseline, 4, 12, 28 and 52 weeks, and 2 weeks post-treatment with ARGS measured by an in-house immunoassay. Change from baseline to week 52 in central medial femorotibial compartment cartilage thickness was measured by magnetic resonance imaging, function and pain by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscores. Associations between cumulative change in ARGS and change in cartilage thickness or WOMAC subscores were evaluated by linear regression. RESULTS: S201086 reduced serum levels of ARGS in a dose-dependent manner throughout the treatment period. Maximal reduction was at 4 weeks with a 58.5% [95% CI 60.8%, 56.2%] reduction of ARGS compared to baseline for 300 mg S201086. Two weeks post-treatment, ARGS concentrations rebounded with a dose-dependent overshoot compared to baseline levels. Cumulative change of ARGS concentration from baseline to week 52 had no effect on change in cartilage thickness (slope -0.8x10(-6) [-2.9x10(-6), 1.3x10(-6)]) or change in WOMAC pain and function (slopes -30x10(-6) [-64x10(-6), 5.2x10(-6)] and -97x10(-6) [-214x10(-6), 20x10(-6)], respectively) at week 52. CONCLUSION: Systemic inhibition of ADAMTS-5 resulted in markedly reduced serum ARGS, but change in serum ARGS concentrations showed no association with the progression of cartilage thinning, or patient reported pain and function. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/fa0caa80-71b6-4215-b0b8-f5ac4e354ae1
- author
- Larsson, Staffan
LU
; Lalande, Agnes
; Lohmander, L Stefan
LU
; Soret, Perrine
; Bernard, Katy
; Pueyo, Maria
and Struglics, André
LU
- organization
- publishing date
- 2024
- type
- Contribution to journal
- publication status
- epub
- subject
- in
- Osteoarthritis and Cartilage
- pages
- 1 - 8
- publisher
- Elsevier
- external identifiers
-
- pmid:38862084
- scopus:85197099878
- ISSN
- 1063-4584
- DOI
- 10.1016/j.joca.2024.06.003
- language
- English
- LU publication?
- yes
- id
- fa0caa80-71b6-4215-b0b8-f5ac4e354ae1
- date added to LUP
- 2024-09-04 23:37:41
- date last changed
- 2024-09-05 08:10:30
@article{fa0caa80-71b6-4215-b0b8-f5ac4e354ae1,
abstract = {{To monitor serum concentrations of the aggrecan alanine-arginine-glycine-serine (ARGS) neoepitope in a clinical trial of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-5 inhibition as disease-modifying therapy of knee osteoarthritis, and to investigate relationships between reduction in ARGS and change in cartilage thickness, knee-related pain and function.<br/><br/>Design<br/>ROCCELLA trial participants received once-daily oral S201086 75, 150 or 300 mg, or placebo, for 52 weeks. Serum was collected at baseline, 4, 12, 28 and 52 weeks, and 2 weeks post-treatment with ARGS measured by an in-house immunoassay. Change from baseline to week 52 in central medial femorotibial compartment cartilage thickness was measured by magnetic resonance imaging, function and pain by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscores. Associations between cumulative change in ARGS and change in cartilage thickness or WOMAC subscores were evaluated by linear regression.<br/><br/>Results<br/>S201086 reduced serum levels of ARGS in a dose-dependent manner throughout the treatment period. Maximal reduction was at 4 weeks with a 58.5% [95% CI 60.8%, 56.2%] reduction of ARGS compared to baseline for 300 mg S201086. Two weeks post-treatment, ARGS concentrations rebounded with a dose-dependent overshoot compared to baseline levels. Cumulative change of ARGS concentration from baseline to week 52 had no effect on change in cartilage thickness (slope −0.8×10−6 [−2.9×10−6, 1.3×10−6]) or change in WOMAC pain and function (slopes −30×10−6 [−64×10−6, 5.2×10−6] and −97×10−6 [−214×10−6, 20×10−6], respectively) at week 52.<br/><br/>Conclusion<br/>Systemic inhibition of ADAMTS-5 resulted in markedly reduced serum ARGS, but change in serum ARGS concentrations showed no association with the progression of cartilage thinning, or patient reported pain and function.}},
author = {{Larsson, Staffan and Lalande, Agnes and Lohmander, L Stefan and Soret, Perrine and Bernard, Katy and Pueyo, Maria and Struglics, André}},
issn = {{1063-4584}},
language = {{eng}},
pages = {{1--8}},
publisher = {{Elsevier}},
series = {{Osteoarthritis and Cartilage}},
title = {{Serum ARGS-aggrecan in a phase 2 clinical trial targeting osteoarthritis}},
url = {{http://dx.doi.org/10.1016/j.joca.2024.06.003}},
doi = {{10.1016/j.joca.2024.06.003}},
year = {{2024}},
}