Immunic AG, Am Klopferspitz 19, 82152 Planegg-Martinsried, Germany.
Immunic AG, Am Klopferspitz 19, 82152 Planegg-Martinsried, Germany.
Mult Scler Relat Disord. 2020 Aug;43:102129. doi: 10.1016/j.msard.2020.102129. Epub 2020 May 6.
Inhibition of dihydroorotate dehydrogenase (DHODH) is an established mechanism for the treatment of relapsing-remitting multiple sclerosis (RRMS). Currently approved treatments have several shortcomings. Consequently, new and effective treatments with improved safety and convenience profiles are sought after by patients.
To explore the overall profile of vidofludimus for the treatment of RRMS.
Preclinical investigations were done exploring the species-dependency of DHODH inhibition of vidofludimus. In addition, the preclinical efficacy in a rat experimental autoimmune encephalomyelitis (EAE) model and the inhibition of cytokine release from activated PBMC were investigated. Pharmacokinetic data were also obtained in a Phase 1 multiple ascending dose trial of the formulation IMU-838 (vidofludimus calcium).
It was shown that vidofludimus is 2.6 times more potent in inhibiting DHO oxidation by human DHODH compared to teriflunomide. Although both compounds increased cell apoptosis, vidofludimus was more efficacious in the inhibition of T-lymphocyte proliferation compared to teriflunomide. The same was also observed for the secretion of IL-17 and IFN-γ. Interestingly, the potency or vidofludimus to inhibit rat or mouse DHODH is 7.5 and 64.4 time lower than the for the human DHODH, respectively. The rat EAE study clearly exhibited a dose-dependent inhibition of cumulative disease scores by vidofludimus. In the multiple ascending dose Phase 1 clinical trial, the serum half-life of about 30 h provides a favorable profile for once daily dosing of IMU-838, with quick dosing to steady state through levels within 5 days and the ability to wash out drug quickly, if required.
The investigations highlighted that the desired selective immunomodulatory properties can be separated from general antiproliferative effects seen and related adverse events in first-generation DHODH inhibitors. Based on data obtained from a series of pre-clinical as well as phase 1 and phase 2 studies, IMU-838 is a promising next-generation candidate for the oral treatment of RRMS. However, this will need to be confirmed in the currently ongoing Phase 2 study in RRMS patients.
二氢乳清酸脱氢酶（DHODH）的抑制作用是治疗复发性缓解型多发性硬化症（RRMS）的一种既定机制。目前批准的治疗方法存在一些缺点。因此，患者希望寻求新的、有效的治疗方法，这些方法具有更好的安全性和便利性。
探讨 vidofludimus 治疗 RRMS 的整体概况。
进行了临床前研究，以探索 vidofludimus 对不同物种 DHODH 抑制的依赖性。此外，还研究了 vidofludimus 在大鼠实验性自身免疫性脑脊髓炎（EAE）模型中的临床前疗效和激活的 PBMC 细胞因子释放的抑制作用。还获得了在 IMU-838（vidofludimus 钙）的 1 期递增剂量试验中的药代动力学数据。
结果表明，与特立氟胺相比，vidofludimus 对人 DHODH 氧化二氢乳清酸的抑制作用要强 2.6 倍。虽然这两种化合物都增加了细胞凋亡，但与特立氟胺相比，vidofludimus 更有效地抑制 T 淋巴细胞增殖。IL-17 和 IFN-γ 的分泌也是如此。有趣的是，vidofludimus 对大鼠或小鼠 DHODH 的抑制效力分别比人 DHODH 低 7.5 和 64.4 倍。大鼠 EAE 研究清楚地表明，vidofludimus 以剂量依赖性方式抑制累积疾病评分。在 1 期递增剂量临床试验中，约 30 小时的血清半衰期为每日一次给药 IMU-838 提供了有利的特征，通过 5 天内达到稳定水平和快速清除药物的能力（如果需要）。
这些研究结果强调，与第一代 DHODH 抑制剂中所见的一般抗增殖作用和相关不良事件相比，可以分离出所需的选择性免疫调节特性。基于一系列临床前以及 1 期和 2 期研究获得的数据，IMU-838 是一种有前途的口服治疗 RRMS 的新一代候选药物。然而，这需要在目前正在进行的 RRMS 患者的 2 期研究中得到证实。
