SEATTLE (EGMN) – Treatment of relapsing-remitting multiple sclerosis with orally administered fingolimod results in a significantly lower annualized relapse, compared with interferon-beta-1a, based on the results of a phase III trial.

A significantly lower percentage of patients who received fingolimod at either of two dosages did not experience relapse in the international, randomized, double-blind, TRANSFORMS (TRial Assessing injectable interferoN vS FTY720 Oral in RrMS) trial. However, safety concerns in regard to two deaths from disseminated herpes zoster and herpes zoster encephalitis that occurred in the higher-dose fingolimod group will be addressed in a related ongoing study, said lead author Dr. Jeffrey Cohen, a neurologist at the Cleveland Clinic in the U.S.A.

“Fingolimod is a sphingosine-1-phosphate (S1P) receptor modulator,” Dr. Cohen said. “It’s the first in a novel class of oral agents that may be therapeutically of benefit in multiple sclerosis.”

The agent, also known as FTY720, has two mechanisms of action, he explained. It promotes retention of lymphocytes in lymph nodes (away from the central nervous system), and it modulates S1P receptors in neural cells.

In the trial, the investigators randomly assigned 431 patients to oral fingolimod 0.5 mg once daily, 425 to oral fingolimod 1.25 mg once daily, and 435 to intramuscular interferon-beta-1a 30 mcg once weekly.

The patients were 36 years old on average, and two-thirds were women, Dr. Cohen reported at the annual meeting of the American Academy of Neurology. They had had MS for about 7.5 years on average, and their mean Expanded Disability Status Scale score was 2.2. Nearly half (45%) had not previously been treated with disease-modifying agents.

The annualized relapse rate at 12 months – the trial’s primary endpoint – was 0.33 in the interferon-beta-1a (IFNbeta-1a) group, 0.16 in the lower-dose fingolimod group, and 0.20 in the higher-dose fingolimod group. This corresponded to a significant 52% and 38% reduction with fingolimod at the lower and higher dose, respectively.

The findings were essentially the same in per-protocol analyses, and in analyses restricted to treatment-naïve patients and to treatment-experienced patients.

In addition, the percentage of patients who did not experience any relapses was significantly greater with lower-dose fingolimod (83%) and higher-dose fingolimod (80%) than with IFNbeta-1a (69%).

On magnetic resonance imaging, compared with their counterparts treated with IFNbeta-1a, patients treated with the lower and higher doses of fingolimod had a smaller mean number of new or newly enlarged T2 lesions (1.5 and 1.4 vs. 2.1) and gadolinium-positive T1 lesions (0.23 and 0.14 vs. 0.51).

The percentage of patients who had a confirmed progression of disability did not differ between groups (8% with IFNbeta-1a and 6% with each dose level of fingolimod).

Serious adverse events occurred in 6% of the IFNbeta-1a group, 7% of the lower-dose fingolimod group, and 11% of the higher-dose fingolimod group.

None of the patients treated with IFNbeta-1a developed bradycardia or atrioventricular block, but 1% and 4% of those treated with lower- and higher-dose fingolimod did. “These are known effects of the first dose of fingolimod related to interaction with S1P receptors in the heart,” Dr. Cohen commented. “Most of these were asymptomatic, and all of these resolved without sequelae.”

Localized skin cancers occurred in 0.4% of the IFNbeta-1a group, 1.4% of the lower-dose fingolimod group, and 0.5% of the higher-dose fingolimod group.

Study drug discontinuation due to adverse events was more common with the higher dose of fingolimod (10%) than with the lower dose (6%) and with IFNbeta-1a (4%). Also, there were two deaths in the higher-dose group – one from disseminated herpes zoster and one from herpes simplex encephalitis – versus none in the other groups.

“This trial met its primary endpoint and demonstrated superiority of fingolimod in both groups over IFNbeta-1a,” Dr. Cohen concluded.

“In general, fingolimod was well tolerated,” he said. “The 0.5-mg dose appeared to be somewhat better tolerated than the 1.25-mg dose, and there were some safety observations that need to be followed up.”

A related, ongoing 2-year trial – FREEDOMS (Fingolimod Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis) – in which fingolimod is being compared with with placebo “will give us a much better indication of the benefit-risk profile,” he added.

Dr. Cohen reported that he has received personal compensation for activities with Novartis (the manufacturer of fingolimod) and Biogen Idec (the manufacturer of IFNbeta-1a). The study was funded by Novartis Pharma AG in Basel, Switzerland.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

西雅图(EGMN)——一项Ⅲ期临床研究显示，在复发-缓解型多发性硬化症（MS）的治疗中，口服芬戈莫德的年复发率显著低于干扰素β-1a（IFNβ-1a）。

在这项名为TRANSFORMS（在复发-缓解型多发性硬化症中评估干扰素注射与口服FTY720的临床试验）的国际性随机双盲研究中，较低和较高剂量芬戈莫德组的未复发患者百分比均显著低于IFNβ-1a组。然而，首席研究员、美国克利夫兰临床医学中心的神经病学家Jeffrey Cohen博士说，较大剂量芬戈莫德组出现的2例死亡病例（1例死于泛发性带状疱疹，1例死于带状疱疹脑炎）也带来了安全性问题，该问题将在另一项正在进行中的相关研究中进一步探讨。

“芬戈莫德是一种鞘氨醇-1-磷酸（S1P）受体调节剂，”Cohen博士说，“是第一个能给MS带来益处的新型口服药物。”

他解释说，芬戈莫德又名FTY720，有两种作用机制，一是促使淋巴细胞回迁至淋巴结（远离中枢神经系统），二是调节神经细胞的S1P受体。

在该试验中，研究者将患者随机分成3组：431例患者口服芬戈莫德0.5 mg，1次/天； 425例患者口服芬戈莫德1.25 mg，1次/天；435例患者肌肉注射IFNβ-1a 30 μg，1次/周。

Cohen博士在2009年美国神经病学会（AAN）年会上报告了该研究结果。患者平均年龄为36岁，2/3为女性，平均多发性硬化症病程为7.5年，平均扩展残疾状态量表（EDSS）评分为2.2。近一半（45%）患者此前从未接受过缓解疾病药物（DMA）的治疗。

该研究的主要终点——12个月时的年复发率，在IFNβ-1a组为0.33，在较低剂量芬戈莫德组为0.16，在较高剂量芬戈莫德组为0.20。相当于较低和较高剂量的芬戈莫德使年复发率分别显著降低了52%和38%。

无论是按方案（PP）分析，还是对初治患者进行的亚组分析，或是对有治疗经历患者进行的亚组分析，结果都与上述结果相同。

此外，较低和较高剂量芬戈莫德组的未复发患者百分比均显著高于IFNβ-1a组，分别为83%、80%和69%。

磁共振成像（MRI）显示，较低和较高剂量芬戈莫德组患者在T2加权像上新出现或新增大病变的平均数目少于IFNβ-1a组（分别为1.5、1.4和2.1），在T1加权像上新出现或新增大的钆阳性病变的平均数目也少于IFNβ-1a组（分别为0.23、0.14和0.51）。

三组中确诊的残疾进展的患者百分比没有显著性差异，IFNβ-1a组为8%，两个芬戈莫德组均为6%。

IFNβ-1a组的严重不良反应发生率为6%，较低和较高剂量芬戈莫德组分别为7%和11%。

IFNβ-1a组没有患者发生窦性心动过缓或房室传导阻滞，但较低和较高剂量芬戈莫德组这类该不良反应发生率分别为1%和4%。“这些都是已知的芬戈莫德的初次给药效应，由该药与心脏上的S1P受体发生相互作用所致”，Cohen博士点评说，“这类不良反应多数是无症状的，且缓解后都不留后遗症。”

IFNβ-1a组的局限性皮肤癌发生率为0.4%，较低和较高剂量芬戈莫德组分别为1.4%和0.5%。

因不良事件而导致停药的发生率在较高剂量芬戈莫德组为最高（10%），较低剂量芬戈莫德组其次（6%），IFNβ-1a组最低（4%）。此外，较高剂量芬戈莫德组有2例死亡，其中1例死于泛发性带状疱疹，另1例低于带状疱疹脑炎，而其他两组都没有死亡病例。

Cohen博士的结论是：“该研究达到了其主要终点，证实了两个芬戈莫德组均优于IFNβ-1a组。”

“总的来说，芬戈莫德耐受性良好，”他说，“0.5 mg剂量的耐受性似乎优于1.25 mg剂量，有一些安全性观察指标还需要进一步随访。”

另一项为期2年的相关研究——FREEDOMS（在多发性硬化症中评估每日口服芬戈莫德治疗效果的研究）正在进行中。在该研究中，芬戈莫德与安慰剂进行比较，“将会给我们提供好得多的收益-风险资料”，他补充说。

Cohen博士报告说他从诺华公司（芬戈莫德的生产厂家）和Biogen Idec（IFNβ-1a的生产厂家）获取个人活动经费。该项研究是由瑞士诺华制药公司赞助的。 

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