Fingolimod and cladribine, the first oral formulations for treating relapsing-remitting multiple sclerosis, proved effective in three phase III clinical trials published online Jan. 20 in the New England Journal of Medicine.

The two drugs have different mechanisms of action, but both target lymphocytes that are potentially autoaggressive against the CNS and both also are believed to promote neuroprotective and reparative processes. In separate multicenter, randomized, double-blind, placebo-controlled clinical trials, both oral medications reduced the rate of multiple sclerosis (MS) relapse, slowed the progression of disability, and decreased the number and severity of brain lesions on MRI.

In one of the studies, fingolimod outperformed interferon beta-1a injections, a widely used treatment for MS. “It is likely that the two oral therapies will be at least as effective as other currently available disease-modifying therapies,” Dr. William M. Carroll wrote in an editorial (N. Engl. J. Med. 2010 Jan. 20 [doi:10.1056/NEJMe0912019]).

Both fingolimod and cladribine had acceptable safety profiles with low rates of adverse events leading to discontinuation of the drugs. However, these rates still were twice as high with active therapy as with placebo (ranging from 8% to 14%), and were associated with patient death in at least two cases.

“Clinicians and patients will need to evaluate the risks and benefits of each of these drugs,” and long-term safety remains a particular concern because patients may need to take them their whole lives, according to Dr. Carroll of Sir Charles Gairdner Hospital, Perth, Australia.

In the first study, which was funded by Novartis Pharma, Dr. Ludwig Kappos of the University of Basel (Switzerland) and his associates compared two doses of daily fingolimod capsules (0.5 mg and 1.25 mg) with a matching placebo in 1,272 patients followed for 2 years at medical centers in 22 countries. The primary end point – the rate of relapse – was 54% lower with the lower dose of the drug and 60% lower with the higher dose, relative to placebo.

Fingolimod was equally effective in patients who had never been treated and those who had already received other treatments for MS. The time to first relapse was significantly longer with active treatment than with placebo, and more patients in the active-treatment group remained relapse free at 2-year follow-up.

Both doses of fingolimod also reduced the risk of disability progression and the time to progression. Scores on two measures of disability either remained stable or improved slightly with fingolimod, but worsened with placebo.

MRI scans showed significantly fewer brain lesions, as well as fewer new or enlarged lesions and a smaller overall volume of lesions, with fingolimod than with placebo. In addition, characteristic reductions in brain volume were 30% smaller with fingolimod, Dr. Kappos and his colleagues reported (N. Engl. J. Med. 2010 Jan. 20 [doi:10.1056/NEJMoa0907839]).

In the second study, which also was funded by Novartis Pharma, Dr. Jeffrey A. Cohen of the Cleveland Clinic’s Mellen Center and his associates compared the same two doses of daily oral fingolimod with intramuscular injections of interferon beta-1a. The investigators conducted follow-up for 1 year with 1,292 patients treated at 172 medical centers in 18 countries.

Compared with interferon beta-1a, the relapse rate was 38% lower with low-dose and 52% lower with high-dose fingolimod. The time to relapse, proportion of relapse-free patients, and proportion with multiple relapses also favored fingolimod.

Fingolimod-treated patients also experienced a similar rate of disability progression, time to disability progression, and MRI findings as those that were reported in the trial conducted by Dr. Kappos and his associates.

In these two studies, serious adverse events were more frequent with fingolimod than with the comparator, and they appeared to be more common at the higher dose of the drug. Adverse events tended to fall into the categories expected for any immunomodulatory agent: lymphocytopenia, CV effects, increased rates of infection, macular edema, liver-enzyme abnormalities, and neoplasms.

Fingolimod caused transient and often asymptomatic bradycardia and atrioventricular block, which likely reflects the drug's ability to bind to receptors in cardiac tissue. The long-term relevance of this effect is not yet known.

The drug also raised the rate of infection, including pneumonia. Several patients developed herpes infections, two of which were fatal, and reactivation of latent herpes remains a concern.

Both research groups emphasized that longer studies are needed to assess safety issues adequately.

In the third study, sponsored by Merck Serono, Dr. Gavin Giovannoni of Queen Mary University, London, and his associates compared two doses of oral cladribine with a matching placebo in 1,326 patients who were followed for 96 weeks at 155 centers in 32 countries.

The agents were given in two or four short courses for 48 weeks, then again in two short courses at weeks 48 and 52, for a total of 8-20 treatment days per year. This schedule allowed for an extended hematopoietic recovery period during the interval before the second round of treatment courses.

Both doses of cladribine significantly reduced the relapse rate by 55%-58%. In addition, the drug lengthened the time to relapse and decreased the rate of disability progression by approximately one-third.

Cladribine also reduced measures of MS inflammatory activity on MRI brain imaging.

The rate of serious adverse events was 8% with low-dose cladribine and 9% with high-dose cladribine, compared with 6% with placebo. The types of adverse events were similar to those with other immunomodulatory agents: lymphocytopenia, infection, and neoplasms.

Twenty patients had reactivation of latent herpes infections, and 1 had a reactivation of latent tuberculosis that proved fatal. “Cancers were isolated cases across different organ systems, and given the small number, it is not possible to establish a risk for the use of cladribine,” Dr. Giovannoni and his colleagues wrote (N. Engl. J. Med. 2010 Jan. 20 [doi:10.1056/NEJMoa0902533]).

As with fingolimod, the risks of treatment with cladribine must be carefully weighed against the benefits, and longer follow-up is essential, the investigators added.

All three clinical trials were well conducted and “provide a new horizon for patients with relapsing-remitting MS and a welcome increase in the range of treatment options,” Dr. Carroll noted.

All three first authors and many of their coauthors reported receiving consulting or lecture fees or research support from many manufacturers of drugs for MS, including Biogen Idec,Merck Serono, EMD Serono, and Novartis.

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

1月20日在线发表于《新英格兰医学杂志》(New England Journal of Medicine)的3项III期临床试验一致表明，首批针对复发-缓解型多发性硬化的口服制剂——芬戈莫德(fingolimod)和克拉屈滨(cladribine)确有疗效。

 

虽然这两种药物的作用机理不同，但都靶向作用于对中枢神经系统(CNS)有潜在自身攻击性的淋巴细胞，并且都可促进神经保护与修复过程。其他多中心、随机、双盲、安慰剂对照临床试验表明，这两种口服药均可降低多发性硬化(MS)的复发率、延缓残疾的进展过程、减少颅内MRI病灶的数量及减轻病灶的严重程度。

 

其中一项研究显示，芬戈莫德优于目前MS的常用治疗药物——干扰素β-1a注射剂。William M. Carroll 博士在评论中写道：“如此看来，这两种口服治疗药物至少与现有的其他病情调节药物同样有效。”(N. Engl. J. Med. 2010 Jan. 20 [doi:10.1056/NEJMe0912019])。

 

芬戈莫德和克拉屈滨的安全性特性均可接受，导致停药的不良事件的发生率均较低。但积极治疗组的这一发生率仍是安慰剂组的2倍(范围8%~14%)，且与至少2例病例死亡相关。

 

位于澳大利亚佩斯的查尔斯爵士盖尔德纳医院的Carroll博士说：“医患双方都需要权衡每种药物的利与弊”，由于患者可能需要终身服药，因此长期安全性尤其值得关注。

 

第1项试验由诺华制药资助，瑞士巴塞尔大学的Ludwig Kappos博士及其同事将两种剂量的芬戈莫德(0.5 mg/d和1.25 mg/d)与相匹配的安慰剂进行了对照，共纳入了来自22个国家的医疗中心的1,272例患者，随访期为2年。主要终点为复发率，小剂量组的复发率比安慰剂组低54%，大剂量组则比安慰剂组低60%。

 

无论是从未接受过治疗的患者，还是已经接受过其他MS治疗的患者，芬戈莫德都同样有效。积极治疗组至首次复发的时间显著晚于安慰剂组，并且2年随访时积极治疗组仍未复发的患者人数多于安慰剂组。

 

两种剂量的芬戈莫德均可降低残疾进展的风险并延缓至进展的时间。芬戈莫德治疗组的两种残疾指标评分均维持恒定或略有改善，但安慰剂组却出现了恶化。

 

Kappos博士及其同事报告称，MRI扫描显示，芬戈莫德治疗组的颅内病灶数量显著少于安慰剂组，新发或扩大的病灶数量更少，病灶的总体积也更小。此外，芬戈莫德治疗组大脑体积特征性缩小的程度也比安慰剂组低30%(N. Engl. J. Med. 2010 Jan. 20 [doi:10.1056/NEJMoa0907839])。

 

第2项试验也是由诺华制药资助，美国克里夫兰诊所Mellen中心的Jeffrey A. Cohen博士及其同事将两种剂量的芬戈莫德口服药(0.5 mg/d和1.25 mg/d)与干扰素β-1a肌肉注射剂进行了对照。研究者共纳入了来自18个国家172个医疗中心的1,292例患者，随访期为1年。

 

小剂量芬戈莫德组的复发率比干扰素β-1a组低38%，大剂量芬戈莫德组则比干扰素β-1a组低52%。从至复发的时间、无复发的患者比例以及多处复发的患者比例来看，芬戈莫德也优于干扰素β-1a。

 

在接受了芬戈莫德治疗的患者中，残疾进展的发生率、至残疾进展的时间以及MRI的检查结果均与Kappos博士及其同事开展的试验所报告的结果相似。

 

在这两项试验中，芬戈莫德治疗组严重不良事件的发生率均高于对照组，且大剂量芬戈莫德组的发生率最高。所出现的不良事件均属于所有免疫调节剂的常见不良事件类型：淋巴细胞减少、对心血管系统的影响、感染的发生率升高、黄斑水肿、肝脏酶异常以及肿瘤。

 

芬戈莫德导致了一过性和通常无症状的心动过缓和房室传导阻滞，这可能反映了该药与心脏组织中的受体相结合的能力。尚不清楚这种效应的长期相关性。

 

芬戈莫德还导致了包括肺炎在内的感染的发生率升高。数名患者出现了疱疹感染，其中2例为致命性感染，潜伏的疱疹再激活也仍然是一大问题。

 

这两个研究小组都强调，尚需开展随访期更长的试验以充分评价药物的安全性问题。

 

第3项试验则由默克雪兰诺公司资助，英国伦敦大学玛丽女王学院的Gavin Giovannoni博士及其同事将两种剂量的克拉屈滨口服药与相匹配的安慰剂进行了对照，共纳入了来自32个国家155个医疗中心的1,326例患者，随访期为96周。

 

前48周的治疗分2或4个短疗程给药，然后在第48周和52周再予以2个短疗程给药，每年的总给药时间为8~20天。这样的给药方案使得在第2轮疗程开始前的间隔期内有一个足够长的造血功能恢复期。

 

两种剂量的克拉屈滨均显著降低了复发率，与安慰剂组相比下降了55%~58%。此外，克拉屈滨还延缓了至复发的时间，并且使残疾进展的发生率下降了大约1/3。

 

头颅MRI成像显示，克拉屈滨还降低了反映MS炎症活性的指标。

 

小剂量克拉屈滨组严重不良事件的发生率为8%，大剂量克拉屈滨组为9%，而安慰剂组为6%。不良事件的类型与其他免疫调节剂类似：淋巴细胞减少、感染和肿瘤。

 

20例患者出现了潜伏的疱疹感染再激活，1例患者出现了潜伏的肺结核再激活且属于致命性不良事件。Giovannoni博士及其同事写道：“个别病例出现了癌症，但位于不同的器官或系统，鉴于出现癌症的病例数很少，因此无法确定使用克拉屈滨会导致癌症风险。” (N. Engl. J. Med. 2010 Jan. 20 [doi:10.1056/NEJMoa0902533])。

 

研究者补充道，与芬戈莫德相同，必须仔细权衡克拉屈滨治疗的利与弊。此外，更长时间的随访也是必不可少的。

 

Carroll博士指出，所有这3项临床试验的实施过程都很严格，它们“为复发-缓解型MS患者带来了新的希望，可供选择的治疗药物将越来越多。”

 

所有3名第一作者以及许多其他作者都声明接受了多家MS治疗药物生产商提供的咨询费、讲课费或研究经费，其中包括Biogen Idec、默克雪兰诺、EMD雪兰诺和诺华公司。

 

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