SILVER SPRING, Maryland (EGMN) – A U.S. Food and Drug Administration advisory panel unanimously agreed that the available data on fingolimod indicated its effectiveness for treating relapsing-remitting multiple sclerosis and that its safety profile, at the proposed dose, justified approval. Fingolimod would be the first oral treatment approved for MS.

On June 11, the FDA’s Peripheral and Central Nervous System Drugs Advisory Panel voted 25 to 0 that fingolimod had been shown to be effective in reducing the frequency of clinical exacerbations in patients with relapsing-remitting MS, and voted 24 to 1 that the clinical trial data provided substantial evidence that it delayed the accumulation of physical disability. Most agreed that it should be a first-line treatment, although the panel recommended that patients undergoing treatment be closely monitored for macular edema and pulmonary toxicity, serious adverse events associated with fingolimod in clinical trials, including at the 0.5 mg daily dose.

Fingolimod is a sphingosine 1-phosphate receptor (S1PR) modulator. It acts on sphingosine 1-phosphate receptors on lymphocytes, resulting in retention of circulating lymphocytes in the lymph nodes, “thereby reducing the recirculation of potentially autoreactive lymphocytes and preventing their infiltration into the CNS,” according to the manufacturer, Novartis Pharmaceuticals Corp. This process is reversible and circulating lymphocytes return to normal levels if treatment is stopped, according to the company.

Novartis has proposed that fingolimod be approved as a disease-modifying therapy for the treatment of patients with relapsing forms of MS to reduce the frequency of clinical exacerbations and to delay the accumulation of physical disability – at a dose of 0.5 mg daily because of the more favorable safety profile and comparable efficacy than 1.25 mg/day, the other dose tested in clinical trials.

Fingolimod – at both the 0.5 mg and 1.25 mg/day dose – was compared to placebo or interferon beta-1a in two studies of more than 2,500 patients with relapsing-remitting MS; the primary end point in both studies was the annualized relapse rate, evaluated over 1 year in one study and 2 years in the second. In both studies, treatment at both doses had a significantly greater effect in reducing relapses when compared to placebo or interferon beta-1a, and also slowed the accumulation of physical disability.

The company dropped plans to pursue approval of the higher dose because of the adverse events, which appear to be dose related. The panel recommended that the company study patients taking a dose lower than 0.5 mg/day.

The main safety issues addressed were bradycardia and heart conduction abnormalities associated with the first dose; macular edema, including at the 0.5 mg dose; and a gradual decline in pulmonary function, effects that appeared to be dose related. There were two herpes-related deaths among the more than 4,000 patients treated with fingolimod to date; these cases were not related to steroid therapy, according to the company.

The company has proposed a 5-year postmarketing safety study of the 0.5 mg dose and also plans pregnancy registry. The company has also filed for approval in the European Union and other countries. The FDA is expected to make a decision by September.

The FDA usually follows the recommendations of its advisory panels. Members of FDA advisory panels have been cleared of potential conflicts of interest by the FDA prior to the meeting, but occasionally, the FDA grants a waiver to a panelist with a conflict of interest.

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

马里兰州银泉(EGMN)——美国食品药品管理局(FDA)顾问专家组得出一致结论，即芬戈莫德的现有数据表明该药是一种用于治疗复发-缓解型多发性硬化症的有效药物，其在推荐剂量下的安全特性已获得认可。芬戈莫德将成为首例被批准用于治疗多发性硬化症(MS)的口服药物。

 

6月11日，FDA周围及中枢神经系统药物顾问专家组以25:0的投票结果通过了如下结论，即相关研究业已证明，芬戈莫德可有效降低复发-缓解型MS患者临床症状恶化的几率，此外，该专家组又以24:1的投票结果通过了另一项结论，即该药的临床试验数据业已提供的大量证据表明，该药可以延缓患者肢体残疾的发病进程。尽管专家组建议应在接受该药治疗患者中对该药所致的黄斑水肿和肺毒性(临床试验显示，芬戈莫德可能与这些严重不良事件有关，包括给药剂量0.5 mg/d时)进行密切监测，但大部分专家均同意将该药用于一线治疗。

 

芬戈莫德是一种鞘氨醇1-磷酸受体(S1PR)调节剂。该药可以作用于位于淋巴细胞上的鞘氨醇1-磷酸受体，致使循环中的淋巴细胞在淋巴结内滞留，“从而减少自身反应性淋巴细胞再次进入循环的几率，进而防止这些细胞浸润中枢神经系统(CNS)，”据该药的制药商诺华制药公司介绍。该过程是可逆的，如果停止用药，循环中的淋巴细胞水平就会恢复正常。

 

诺华公司已建议FDA批准将芬戈莫德作为一种改善病情的治疗药物用于治疗患有复发型MS的患者，以降低这些患者临床症状恶化的发生率，并且延缓其肢体残疾的病程进展速度——给药剂量为0.5 mg/d，因为与1.25 mg/d的给药剂量(及该临床试验检测的其他剂量)相比，在该剂量下药物产生的疗效类似且安全性更佳。

 

 在两项总计纳入超过2,500例复发-缓解型MS患者的研究中，研究者对芬戈莫德(给药剂量为0.5与1.25 mg/d)和安慰剂或干扰素β -1a 进行了对比，两项研究的主要终点均为年化复发率，其中一项研究的评估时间在研究开始1年后，另一项则在研究开始2年后。在两项研究中，与安慰剂或干扰素β -1a相比，该药物在两种给药剂量下均能使患者的复发率显著降低，并减缓患者肢体残疾的病程进展速度。

 

因为更高给药剂量导致的不良事件，该公司已经放弃向FDA申请高剂量许可的计划，因为这些不良事件似乎与给药剂量有关。该专家组建议诺华公司对低于0.5  mg/d的给药剂量加以研究。

 

该研究指出，该药的主要安全问题是首次用药可能引起心动过缓和心脏传导功能异常，黄斑水肿(包括给药剂量为0.5 mg时)和肺功能逐步下降，这些效应似乎均与剂量相关。到目前为止，在应用过芬戈莫德的超过4,000例患者中已出现2例疱疹致死病例，这些病例与类固醇治疗无关，据该公司介绍。

 

该公司业已打算针对0.5 mg的给药剂量进行为期5年的上市后药物安全性研究，其还计划进行妊娠登记项目。该公司同时已经申请欧盟及其他国家对该药进行审批。FDA预期将于9月作出决定。

 

FDA通常会遵循其顾问专家组的推荐意见。在会议召开前，FDA已确定其顾问专家组成员均不存在潜在利益冲突，但有时，FDA会准许某位存在利益冲突的顾问专家组成员弃权。

 

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