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Investigation of the activity of vidofludimus calcium, a novel, orally available, small molecule inhibitor of dihydroorotate dehydrogenase, as a treatment for primary sclerosing cholangitis (PSC)

研究维氟地莫钙（一种新型口服二氢乳清酸脱氢酶小分子抑制剂）治疗原发性硬化性胆管炎 (PSC) 的活性

基本信息

批准号：
10312499
负责人：
Elizabeth Carey
金额：
$ 12.99万
依托单位：
MAYO CLINIC ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-05 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10312499
关键词：
Investigation activity vidofludimus calcium novel

项目摘要

SUMMARY Primary sclerosing cholangitis (PSC) is an idiopathic disease of the liver characterized by ongoing inflammation of the intrahepatic and/or extrahepatic bile ducts. PSC is a rare, but debilitating disease, with a prevalence of roughly 50,000 patients in the United States. The outcome in patients with PSC is highly unsatisfactory, with many cases ultimately leading to cirrhosis, cancer of the liver or bile duct, or end-stage liver disease. PSC is one of the leading indications for liver transplantation in the US and many European countries, with a median time from diagnosis to death or liver transplantation of only 8 years. To date, no medical therapies other than liver transplantation have been proven to halt the progression of the disease. PSC often exhibits comorbidity with inflammatory bowel disease (IBD), particularly ulcerative colitis (UC). IBD is present in 70%-80% of PSC patients, with 90% of that in the form of UC. PSC and IBD share a strong link to the proinflammatory cytokine IL-17 and Th17 cells, IL-17-producing lymphocytes. In IBD, Th17 cells massively infiltrate the inflamed intestine and UC patients demonstrate greatly increased expression of IL-17 in colonic mucosa. Recent studies now also indicate a central role of IL-17 in the pathogenesis of PSC. The investigational new drug vidofludimus calcium (VC) is a new small molecule immune modulator that has been shown to induce apoptosis in proliferating lymphocytes and reduce release of the proinflammatory cytokines IL-17 and IFNγ. This is accomplished through its potent inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), which catalyzes the rate-limiting step in the pyrimidine synthesis pathway. Metabolic stress secondary to this inhibition leads to these key immunomodulatory effects. As DHODH is highly expressed in activated lymphocytes, whereas resting lymphocytes are able to meet their pyrimidine needs through the DHODH-independent salvage pathway, VC selectively affects activated immune cells. In a recent clinical trial, vidofludimus has demonstrated a strong positive effect in patients with ulcerative colitis, and a series of clinical trials have demonstrated a highly favorable safety profile. Based on the above evidence, we believe that VC is likely to serve as a safe and effective therapy in patients with PSC, and that a small-scale trial to test this hypothesis is warranted. Here we propose a 30 patient, open- label, single-arm 6-month study of VC in PSC patients. The study will be conducted by a team of investigators with a long history of involvement in PSC research and clinical trials. The trial will be carried out at two sites, each of which is recognized as a tertiary referral center for PSC. Success in this trial would motivate larger, more comprehensive clinical trials. This may eventually lead to an effective therapy for this rare but deadly disease where one does not currently exist, significantly improving patient outcome and quality of life.

摘要原发性硬化性胆管炎(PSC)是一种特发性肝脏疾病，其特征是持续肝内和/或肝外胆管发炎。PSC是一种罕见的但使人虚弱的疾病，具有在美国大约有5万名患者。PSC患者的预后很高不令人满意，许多病例最终导致肝硬变、肝癌或胆管癌或终末期肝病。在美国和许多欧洲国家，PSC是肝移植的主要适应症之一从确诊到死亡或肝移植的中位数时间只有8年。到目前为止，没有除了肝移植之外的其他医学疗法已经被证明可以阻止疾病的发展。 PSC常与炎症性肠病(IBD)共病，尤其是溃疡性结肠炎(UC)。IBD 在70%-80%的PSC患者中存在，其中90%以UC的形式存在。PSC和IBD有很强的联系促炎症细胞因子IL-17和Th17细胞、产生IL-17的淋巴细胞。在IBD中，Th17细胞大量炎性肠炎和UC患者IL-17表达显著增加结肠粘膜。最近的研究也表明IL-17在PSC的发病机制中起着中心作用。正在研究的新药Vc是一种新的小分子免疫调节剂，具有已被证明可以诱导增殖中的淋巴细胞凋亡，并减少促炎因子的释放细胞因子IL-17和干扰素γ。这是通过它对线粒体酶的有效抑制来实现的。二氢核酸脱氢酶(DHODH)，催化嘧啶合成中的限速步骤路径。继发于这种抑制的代谢应激导致了这些关键的免疫调节效应。AS DHODH在激活的淋巴细胞中高度表达，而静止的淋巴细胞能够满足其嘧啶需要通过DHODH非依赖的挽救途径，VC选择性地影响激活的免疫细胞。在最近的一项临床试验中，Vidofludimus对患有慢性阻塞性肺疾病的患者显示出很强的积极效果溃疡性结肠炎和一系列临床试验已经证明了非常有利的安全性。基于上述证据，我们认为VC很可能成为一种安全有效的治疗方法因此，有必要进行小规模试验来检验这一假说。在这里，我们建议30名患者，开放- LABEL，单臂6个月的PSC患者VC研究。这项研究将由一个调查小组进行有参与PSC研究和临床试验的悠久历史。试验将在两个地点进行，其中每一个都被认为是PSC的第三转诊中心。这场试验的成功将激励更大的，更全面的临床试验。这可能最终导致一种治疗这种罕见但致命的疾病的有效方法目前尚不存在的疾病，显著改善了患者的预后和生活质量。