A phase 2 trial investigating the efficacy and safety of the mPGES-1 inhibitor vipoglanstat in systemic sclerosis-related Raynaud's.

IF 4.7 2区医学 Q1 RHEUMATOLOGY

Rheumatology Pub Date : 2025-02-01 DOI:10.1093/rheumatology/keae049

Göran Tornling, Charlotte Edenius, John D Pauling, Christopher P Denton, Anna Olsson, Jan Kowalski, Andrea Murray, Marina Anderson, Smita Bhat, Francesco Del Galdo, Frances Hall, Mariusz Korkosz, Dorota Krasowska, Jacek Olas, Vanessa Smith, Jacob M van Laar, Madelon C Vonk, Anna Wojteczek, Ariane L Herrick

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引用次数: 0

Abstract

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.

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一项 2 期试验，研究 mPGES-1 抑制剂维博司他对与系统性硬化症相关的雷诺氏症的疗效和安全性。

研究目的我们的目的是在一项双盲安慰剂对照研究中验证维普司他能改善RP的假设，维普司他是一种微粒体前列腺素E合成酶-1（mPGES-1）抑制剂，能减少前列腺素E2（PGE2）并增加前列环素的生物合成：系统性硬化症（SSc）患者在基线检查前的最后一周内RP发作次数≥7次，随机接受维普司他120毫克或安慰剂治疗4周。每日电子日记记录雷诺氏症发作情况（持续时间和疼痛）和雷诺氏症状况评分，并将雷诺氏症发作次数/周的变化作为主要终点。在基线和治疗结束时进行冷挑战评估。探索性终点包括患者和医生对变化的总体印象、硬皮病相关雷诺现象评估问卷、mPGES-1活性和花生四烯酸代谢物的尿排泄量：69名受试者接受了维博司他（33人）或安慰剂（36人）治疗。平均每周RP发作次数（基线；维普氮芥14.4[标度6.7]次，安慰剂18.2[12.6]次）分别减少了3.4[95% CI -5.8;-1.0]次和4.2[-6.5;-2.0]次（p= 0.628）。所有患者报告的结果均有所改善，组间无差异。冷挑战后外周血流恢复的平均变化在研究组之间没有差异。维普司坦能完全抑制 mPGES-1，使尿液中的 PGE2 减少 57%，前列环素代谢物增加 50%。结论：维普格兰司他安全且耐受性良好：尽管维普格司他安全且耐受性良好，其剂量可完全抑制 mPGES-1，但对 SSc 相关 RP 无效。因此，vipoglanstat 的进一步开发和评估将在 mPGES-1 起致病作用的其他疾病中进行。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Rheumatology 医学-风湿病学

CiteScore

9.40

自引率

7.30%

发文量

1091

审稿时长

2 months

期刊介绍： Rheumatology strives to support research and discovery by publishing the highest quality original scientific papers with a focus on basic, clinical and translational research. The journal’s subject areas cover a wide range of paediatric and adult rheumatological conditions from an international perspective. It is an official journal of the British Society for Rheumatology, published by Oxford University Press. Rheumatology publishes original articles, reviews, editorials, guidelines, concise reports, meta-analyses, original case reports, clinical vignettes, letters and matters arising from published material. The journal takes pride in serving the global rheumatology community, with a focus on high societal impact in the form of podcasts, videos and extended social media presence, and utilizing metrics such as Altmetric. Keep up to date by following the journal on Twitter @RheumJnl.