fingolimod---原发性多发性硬化患者的福音

2008年4月16日--在刚结束的持续三年的新药临床试验中显示：70%的多发性硬化受试者在服用试验新药FTY720--FINGOLIMOD后，有效减少多发性硬化的复发率。

这项研究结果来自于由正在接受免疫抑制治疗的多发性硬化患者参与的2期临床试验。研究者：Researchers  Giancarlo  Comi,来自意大利米兰的San Raffaele医院的主任医师在芝加哥进行的American Academy of Neurology每周例会上报道了这个研究结果。

“现行一线治疗多发性硬化的药物，只能减少复发率30%左右，因此这项研究结果将会是人类治疗多发性硬化历史上的一个里程碑。”Comi在例会上说道。

芬戈莫德FTY-720是从蝉幼虫的子囊菌培养液中提取的抗生素成分ISP-I经化学修饰后合成的新型免疫抑制剂，化学名为2-(4-正辛基苯乙基)-2-氨基丙二醇盐酸盐，结构式见图l。

图芬戈莫德 FTY-720的结构式

芬戈莫德FTY-720为鞘氨醇-l-磷酸(s1P)受体调节剂，在体内经磷酸化后与淋巴细胞表面的s1P受体结合，改变淋巴细胞的迁移，促使细胞进入淋巴组织，阻止其离开淋巴组织进入移植物，从而达到免疫抑制的效果。

Budde等的研究表明，FTY-20单次口服给药(0．25-3．5mg/d)，能引起可逆性淋巴细胞减少，且患者耐受性良好。FTY．720不仅能有效预防排斥反应的发生，对已经发生的排斥反应也可以起到一定的逆转效应，并能显著延长移植物的生存时间，而且FTY-720与环孢素csA和普乐可复FK506具有协同抑制作用。

在salvadori等的研究中，FTY-720(5．0mg，qd)与低剂量CsA(3—4mg/d/kg)联合治疗肾移植排斥反应，因急性排斥反应发生率明显升高而被迫提前终止。虽然FTY-720(2．5mg，qd)与全剂量CsA(8一10mg/d/kg)对肾移植急性排斥反应的联合治疗效果与MMF(1g，bid)和全剂量csA的联合治疗效果相当，但FTY-720治疗组肾功能降低、黄斑水肿、心动过缓、肌肝清除率降低以及呼吸道阻力增加等不良反应的发生率较MMF组明显升高。为此，诺华公司终止了FTY-720治疗肾移植排斥反应的进一步研究。但芬戈莫德FTY-720作为第一个slP受体调节剂，为免疫抑制剂的开发提供了新的思路。目前，诺华公司仍在继续进行其他slP受体调节剂的研究与开发

临床II期试验数据显示新药FTY720对治疗多发性硬化症有疗效。

发表在近期新英格兰医学杂志（New England Journal of Medicine）上的关于FTY720 (Fingolimod)的临床研究数据显示，这种一天一次的口服新药对治疗各种复发性多发性硬化症（multiple sclerosis，MS）具有良好的疗效。鉴于II期临床研究的乐观结果，Novartis已经开始III期临床研究以深入评价FTY720在复发性多发性硬化症方面的疗效。
 
临床II期试验数据显示，在试验的前六个月当中，每天服用一次FTY720的试验组相对于服用安慰剂对照组来说可以降低80％的炎症（实验结果由磁共振成象仪器测得），也至少能够减少50％的复发率。之后的六个月当中，继续服用FTY720的病人炎症活动和复发率保持在一个较低的水平，同样的结果也出现在试验后期由服用安慰剂转服FTY720的病人身上。

负责该项研究的瑞士University Hospital Basel的神经科学系博士Ludwig Kappos认为，临床II期试验结果显示FTY720能够显著降低炎症和多发性硬化症的复发率。假如在扩大的III期临床实验中这样的结果能够得到再次的证实，那么FTY720就代表了在多发性硬化症治疗领域的一大进步，成为治疗多发性硬化症的希望。
最近开始的名为FREEDOMS 的临床III期试验将在世界各地100多个研究中心展开，涉及2，000多名病人。试验将采用随机双盲设计，对两种剂量 (1.25 mg 和 0.5 mg)FTY720的有效性和安全性进行评价。

美国FDA顾问专家组同意批准用于治疗多发性硬化症的新型口服药（2010年6月19日）

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。

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。

EAST HANOVER, N.J., Oct. 12, 2007- New preclinical data presented at European Committee for Treatment and Research of Multiple Sclerosis (ECTRIMS) in Prague suggests that FTY720 (fingolimod) directly reduces neurodegeneration and enhances repair of the central nervous system (CNS) damage caused by multiple sclerosis (MS) by interacting with sphingosine-1-phosphate receptors (S1P-R) expressed on brain cells.

This mechanism of action may be in addition to the established anti-inflammatory role of FTY720 that is mediated by the reduction of inflammatory immune cells, called lymphocytes, from reaching the brain.

FTY720 is a novel, once-daily, oral treatment currently in worldwide Phase III clinical development to test its safety and efficacy as a disease modifying therapy for relapsing-remitting MS, which affects approximately 85% of people with multiple sclerosis.

The potential direct beneficial effect of FTY720 in the CNS is supported by the results of several preclinical experiments being presented at ECTRIMS, including research in animal models of MS and in vitro studies on CNS cells called oligodendrocytes.

In an animal model of MS (experimental autoimmune encephalomyelitis in rats), the administration of FTY720 directly into the CNS resulted in a statistically significant reduction in disease severity. This decrease in disease activity was seen in the absence of a reduction of lymphocytes in the bloodstream, suggesting that the favorable effect of FTY720 seen in this model is due to a direct effect in the CNS that is independent of the effects on peripheral lymphocytes.

In two experiments presented at ECTRIMS, the modulation of S1P-R by the addition of FTY720 resulted in an increase in the number, growth and survival of oligodendrocytes in cell culture. This effect of FTY720 on oligodendrocytes may help limit destruction of myelin and promote its repair and, thus, may contribute to the effectiveness of FTY720 in MS. Oligodendrocytes are cells in the CNS that make a fatty tissue, called myelin, which is necessary for normal signal transfer along nerve fibers in the CNS. Myelin and oligodendrocytes are typically damaged in MS.

"FTY720 crosses the blood-brain barrier and the drug's target - S1P receptors - are present on brain cells, including oligodendrocytes as shown in animal cell studies," said Jack Antel, Professor, Department of Neurology and Neurosurgery, McGill University, Montreal, Canada. "We are able to confirm that FTY720 directly modulates the S1P receptors on human oligodendrocyte progenitor cells."

FTY720 is currently being investigated in the largest worldwide Phase III clinical trial program to be conducted in MS to evaluate further its efficacy and safety as a disease modifying therapy for relapsing-remitting MS. This comprehensive program includes trials referred to as FREEDOMS, FREEDOMS II and TRANSFORMS. Recruitment is complete for FREEDOMS and TRANSFORMS. Recruitment is ongoing and on track for FREEDOMS II and FTY720 regulatory filing is planned for the second half of 2009. For more information about the clinical trial program, including eligibility criteria and location of U.S. study sites, patients can call the following toll-free number: 866-788-3930, or visit .

"Novartis has a significant long-term investment and commitment to multiple sclerosis and neuroscience through its extensive research and development program," said Ludwig Hantson, PhD, Senior VP for Commercial Development & Specialty Businesses at Novartis Pharmaceuticals Corporation. "We believe oral FTY720 is an exciting and promising experimental therapy for MS as shown by the compelling Phase II data. As an oral therapy with a novel mechanism of action and promising efficacy, FTY720 has the potential to be a significant and innovative therapeutic advance."

Phase II Study Results

The six-month, placebo-controlled Phase II study conducted in 281 patients with relapsing MS in 11 countries (Europe and Canada) showed that oral FTY720, taken once-daily, reduced relapse rates by more than 50% compared to placebo and reduced MRI (magnetic resonance imaging) measures of inflammation with approximately 80% of patients free of active brain lesions.

In patients continuously treated with FTY720 for up to two years (placebo-controlled study plus the extension trial), up to 77% of patients were relapse-free and more than 80% of patients were free of active brain lesions at two years.

In the six-month placebo-controlled phase of the Phase II study, the most frequent adverse events reported for FTY720 were dose-dependent upper respiratory tract infections (mainly nasopharyngitis) and dyspnea, plus diarrhea and nausea. FTY720 treatment was associated with initial dose-dependent decreases in heart rate and expiratory air flow. Clinically asymptomatic increases in alanine aminotransferase (liver enzyme) and an increase in blood pressure were also observed. No unexpected adverse events emerged in patients treated for up to 24 months compared with the six-month placebo-controlled phase. There was no further elevation of blood pressure with continued treatment beyond the effect seen at six months.

The ongoing Phase III study program includes comprehensive monitoring, which will provide further characterization of the safety profile of FTY720.

Multiple Sclerosis

MS is the most common disorder of the CNS in young adults, affecting more than an estimated 2.5 million people worldwide. It is a progressive and debilitating disorder caused by the destruction of myelin, which helps neurons carry electrical signals in the brain. MS causes problems with muscle control and strength, vision, balance, sensation and mental function. MS typically presents in relapsing forms involving acute self-limiting attacks of neurological dysfunction (or "relapses") followed by complete or partial restoration of functions.

Disclaimer

This release contains certain forward-looking statements relating to Novartis' business, which can be identified by the use of forward-looking terminology such as "may," "suggests," "suggesting," "potential," "promising," "planned" or similar expressions, or by express or implied statements regarding the potential approval of FTY720 by health authorities for marketing, whether or not FTY720 will be the first orally effective MS treatment, the potential health effects or long-term impact of a patient's use of FTY720, or potential future revenue from FTY720. Such forward-looking statements reflect the current views of Novartis regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with FTY720 to be materially different from any future results, performance or achievements expressed or implied by suchstatements.

There can be no guarantee that FTY720 will be approved for any indications or labeling in any market. Neither can there be any guarantee that, if approved, it will be the first orally effective MS treatment. Neither can there be any guarantee regarding the health effects or long-term impact of a patient's use of FTY720. Neither can there be any guarantees that FTY720 will reach any particular levels of revenue. In particular, management's expectations regarding FTY720 could be affected by, among other things, unexpected clinical trial results, including new clinical trial results and additional analysis of existing results; unexpected regulatory actions or delays or government regulation generally; competition in general; Novartis' ability to obtain or maintain patent or other proprietary intellectual property protection; government, industry and general public pricing pressures, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.