Research output: Contribution to Journal/Magazine › Journal article › peer-review
Research output: Contribution to Journal/Magazine › Journal article › peer-review
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TY - JOUR
T1 - A phase 2 trial investigating the efficacy and safety of the mPGES-1 inhibitor vipoglanstat in systemic sclerosis-related Raynaud's
AU - Tornling, Göran
AU - Edenius, Charlotte
AU - Pauling, John D
AU - Denton, Christopher P
AU - Olsson, Anna
AU - Kowalski, Jan
AU - Murray, Andrea
AU - Anderson, Marina
AU - Bhat, Smita
AU - Del Galdo, Francesco
AU - Hall, Frances
AU - Korkosz, Mariusz
AU - Krasowska, Dorota
AU - Olas, Jacek
AU - Smith, Vanessa
AU - van Laar, Jacob M
AU - Vonk, Madelon C
AU - Wojteczek, Anna
AU - Herrick, Ariane L
PY - 2025/2/1
Y1 - 2025/2/1
N2 - Objective Our objective was to test the hypothesis, in a double-blind, placebo-controlled study that vipoglanstat, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1), which decreases prostaglandin E2 (PGE2) and increases prostacyclin biosynthesis, improves RP. Methods Patients with SSc and ≥7 RP attacks during the last screening week prior to a baseline visit were randomized to 4 weeks treatment with vipoglanstat 120 mg or placebo. A daily electronic diary captured RP attacks (duration and pain) and Raynaud’s Condition Score, with change in RP attacks/week as the primary end point. Cold challenge assessments were performed at baseline and end of treatment. Exploratory end points included patients’ and physicians’ global impression of change, Assessment of Scleroderma-associated Raynaud’s Phenomenon questionnaire, mPGES-1 activity, and urinary excretion of arachidonic acid metabolites. Results Sixty-nine subjects received vipoglanstat (n = 33) or placebo (n = 36). The mean weekly number of RP attacks [baseline; vipoglanstat 14.4 (S.D. 6.7), placebo 18.2 (12.6)] decreased by 3.4 (95% CI –5.8; –1.0) and 4.2 (–6.5; –2.0) attacks per week (P = 0.628), respectively. All patient-reported outcomes improved, with no difference between the groups. The mean change in recovery of peripheral blood flow after the cold challenge did not differ between the study groups. Vipoglanstat fully inhibited mPGES-1, resulting in 57% reduction of PGE2 and 50% increase of prostacyclin metabolites in the urine. Vipoglanstat was safe and well tolerated. Conclusion Although vipoglanstat was safe, and well tolerated in a dose achieving full inhibition of mPGES-1, it was ineffective in SSc-related RP. Further development and evaluation of vipoglanstat will therefore be in other diseases where mPGES-1 plays a pathogenetic role. Trial registration ClinicalTrials.gov, https://www.clinicaltrials.gov, NCT0474420.
AB - Objective Our objective was to test the hypothesis, in a double-blind, placebo-controlled study that vipoglanstat, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1), which decreases prostaglandin E2 (PGE2) and increases prostacyclin biosynthesis, improves RP. Methods Patients with SSc and ≥7 RP attacks during the last screening week prior to a baseline visit were randomized to 4 weeks treatment with vipoglanstat 120 mg or placebo. A daily electronic diary captured RP attacks (duration and pain) and Raynaud’s Condition Score, with change in RP attacks/week as the primary end point. Cold challenge assessments were performed at baseline and end of treatment. Exploratory end points included patients’ and physicians’ global impression of change, Assessment of Scleroderma-associated Raynaud’s Phenomenon questionnaire, mPGES-1 activity, and urinary excretion of arachidonic acid metabolites. Results Sixty-nine subjects received vipoglanstat (n = 33) or placebo (n = 36). The mean weekly number of RP attacks [baseline; vipoglanstat 14.4 (S.D. 6.7), placebo 18.2 (12.6)] decreased by 3.4 (95% CI –5.8; –1.0) and 4.2 (–6.5; –2.0) attacks per week (P = 0.628), respectively. All patient-reported outcomes improved, with no difference between the groups. The mean change in recovery of peripheral blood flow after the cold challenge did not differ between the study groups. Vipoglanstat fully inhibited mPGES-1, resulting in 57% reduction of PGE2 and 50% increase of prostacyclin metabolites in the urine. Vipoglanstat was safe and well tolerated. Conclusion Although vipoglanstat was safe, and well tolerated in a dose achieving full inhibition of mPGES-1, it was ineffective in SSc-related RP. Further development and evaluation of vipoglanstat will therefore be in other diseases where mPGES-1 plays a pathogenetic role. Trial registration ClinicalTrials.gov, https://www.clinicaltrials.gov, NCT0474420.
KW - Adult
KW - Aged
KW - Dinoprostone
KW - Double-Blind Method
KW - Epoprostenol/analogs & derivatives
KW - Female
KW - Humans
KW - Male
KW - Middle Aged
KW - Prostaglandin-E Synthases/antagonists & inhibitors
KW - Raynaud Disease/drug therapy
KW - Scleroderma, Systemic/drug therapy
KW - Treatment Outcome
U2 - 10.1093/rheumatology/keae049
DO - 10.1093/rheumatology/keae049
M3 - Journal article
C2 - 38291895
VL - 64
SP - 704
EP - 713
JO - Rheumatology
JF - Rheumatology
SN - 1462-0324
IS - 2
ER -