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zoom RSS 多発性硬化症の経口治療薬/cladribine fingolimod 冬虫夏草

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 2つの治験で有望な結果が出たため、多発性硬化症の経口治療薬が2011年にも使用可能になる可能性がある。18ヶ国で1,000人以上の人に対して治験が行われ、cladribineとfingolimodは2年で50-60%再発率を下げる効果がみられた。fingolimodはインターフェロン1αとの比較も行われ、1年間での再発率減少は2倍であった。
 若年成人に障害をきたす神経疾患で最も多く、英国で10万人以上、全世界で250万人が罹患している。歩行障害、膀胱直腸障害、視力障害をきたす。現在の治療の問題点は注射薬であることにある。
 副作用としてヘルペスやガンのリスクを増大させる可能性があり、治療費の増加が問題となる。薬価を適切に設定することが望まれる。
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画像 冬虫夏草の一種であるlasaria sinclairii菌が産生する免疫抑制作用を持つミリオシン(myriocin)は日本で発見されたが、FTY720(fingolimod)はミリオシンの毒性を軽減するため、化学修飾により創製された化合物。細胞障害を引き起こすT細胞に直接作用することが特徴。リンパ球をリンパ節に閉じ込めて病変部から隔離することで作用する、新しいクラスの免疫抑制剤と見なされている。

冬虫夏草の抗がん作用
http://kurie.at.webry.info/200912/article_38.html
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2005.10.03
日本発の免疫抑制剤FTY720、多発性硬化症対象の臨床試験で有望結果 
http://medical.nikkeibp.co.jp/inc/all/hotnews/archives/401149.html
 スイスNovartis社は10月1日、三菱ウェルファーマから導入した免疫抑制剤FTY720が、多発性硬化症を対象にしたフェーズ2臨床試験で有望な結果が得られたと発表した。Novartis社は2005年末までにフェーズ3試験開始を目指している。なお、わが国では腎移植を対象にした臨床開発は行われているが、多発性硬化症を対象には行われていない。フェーズ2臨床試験の結果は、ギリシャで開催されたECTRIMS/ACTRIMS会議で発表された。
 FTY720は、冬虫夏草の一種であるlasaria sinclairii菌が産生するミリオシン(myriocin)をリード化合物として、化学修飾により創製された化合物。細胞障害を引き起こすT細胞に直接作用することが特徴で、既存の単剤もしくは既存の免疫抑制剤と併用することで、臓器移植の拒絶反応抑制や自己免疫疾患などの治療薬になると期待されている製剤だ。
 フェーズ2試験は欧州とカナダの11カ国32施設で行われた。まず281人の患者をプラセボ投与群、FTY720の 1.25mg投与群、FTY720の5mg投与群に分けて1日1回経口で投与した。プラセボ群は6カ月終了後にFTY720の1.25mgもしくは5mg をさらに6カ月投与した。すでにFTY720投与群も継続して6カ月投与を行った。
 その結果、FTY720投与群は、6カ月投与時点でプラセボ群と比べて再発率が50%以上低下し、その状態は継続投与した6カ月の間も維持されていた。プラセボからFTY720に切り替えた群では、最初のプラセボを投与した期間に比べて、後半の6カ月間で、再発率が少なくとも70%低下したという。
 またMRI(磁気共鳴画像)を用いた解析では、12カ月の時点でFTY720を投与したすべての群で炎症活性の低下がみられた。プラセボからFTY720に変更した患者では、12カ月時点での炎症部位領域は80%以上減少していた。FTY120を12カ月まで投与した群では炎症活性を示す領域がなくなった患者が80%以上となったという。(横山勇生)

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Page last updated at 23:00 GMT, Wednesday, 20 January 2010
Hope for MS pill after cladribine and fingolimod trials
http://news.bbc.co.uk/2/hi/health/8470138.stm

MS patient
Patients would welcome an oral treatment, doctors say

Oral drugs to treat multiple sclerosis could become available in 2011 after promising results in two trials.
Drug licences have been applied for and the MS Society said it was "great news" for people with MS - current treatments involve injections or infusions.
The trials of the drugs each involved 1,000 people in over 18 countries, the New England Journal of Medicine says.
Cladribine and fingolimod, which come as tablets, cut relapse rates by 50-60% over two years compared with placebos.
Fingolimod was also tested against the widely used injection, beta interferon 1a. The trial showed the new drug was twice as effective in reducing the number of relapses over a year.

The evidence is now there and we will be working with the relevant authorities to make sure those who will benefit can get access
Dr Doug Brown, Biomedical Research Manager at the MS Society

Multiple sclerosis is the most common disabling neurological disorder affecting young adults. It affects more than 100,000 people in the UK and 2.5 million worldwide.
Symptoms include mobility problems, lack of bladder and bowel control and and blurred vision.
The downside of current treatments is that they have to be injected or given by infusion.
MS sufferers have long hoped a pill would be developed. Pharmaceutical companies have been competing to get there first.

More choice
Dr Doug Brown, Biomedical Research Manager at the MS Society, said: "This is great news for people with MS and signifies a shifting tide in the treatment of the condition.
"Availability of oral therapies will give people greater choice and being able to take a tablet instead of unpleasant injections will come as welcome relief.
"The evidence is now there and we will be working with the relevant authorities to make sure those who will benefit can get access."
Doctors have also welcomed the studies.
Dr Belinda Weller, a consultant neurologist based in Edinburgh who specialises in MS, said the findings are "very significant" and indicated "a big breakthrough".
"This is the first major advance in MS therapy for a few years," she said. "I hope the drugs will soon be licensed."
But she expressed concerns both about possible side effects - which the trials suggested could include an increased risk of herpes and cancer - and that the new drugs could push up the cost of treating MS.
"More patients are likely to want to use these new drugs," she said. "Some people shun the currently available treatments because of the need to inject. This could put pressure on hospital budgets."
The MS Society called on the drug companies to price the drugs reasonably.
"The evidence is now here and we hope to see the pharmaceutical companies price these drugs responsibly so they can be made available to people with MS."

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Published at www.nejm.org January 20, 2010 (10.1056/NEJMoa0909494)

A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis
Ludwig Kappos, M.D., Ernst-Wilhelm Radue, M.D., Paul O'Connor, M.D., Chris Polman, M.D., Reinhard Hohlfeld, M.D., Peter Calabresi, M.D., Krzysztof Selmaj, M.D., Catherine Agoropoulou, Ph.D., Malgorzata Leyk, Ph.D., Lixin Zhang-Auberson, M.D., Ph.D., Pascale Burtin, M.D., Ph.D., for the FREEDOMS Study Group

ABSTRACT

Background Oral fingolimod, a sphingosine-1-phosphate--receptor modulator that prevents the egress of lymphocytes from lymph nodes, significantly improved relapse rates and end points measured on magnetic resonance imaging (MRI), as compared with either placebo or intramuscular interferon beta-1a, in phase 2 and 3 studies of multiple sclerosis.

Methods In our 24-month, double-blind, randomized study, we enrolled patients who had relapsing--remitting multiple sclerosis, were 18 to 55 years of age, had a score of 0 to 5.5 on the Expanded Disability Status Scale (which ranges from 0 to 10, with higher scores indicating greater disability), and had had one or more relapses in the previous year or two or more in the previous 2 years. Patients received oral fingolimod at a dose of 0.5 mg or 1.25 mg daily or placebo. End points included the annualized relapse rate (the primary end point) and the time to disability progression (a secondary end point).

Results A total of 1033 of the 1272 patients (81.2%) completed the study. The annualized relapse rate was 0.18 with 0.5 mg of fingolimod, 0.16 with 1.25 mg of fingolimod, and 0.40 with placebo (P<0.001 for either dose vs. placebo). Fingolimod at doses of 0.5 mg and 1.25 mg significantly reduced the risk of disability progression over the 24-month period (hazard ratio, 0.70 and 0.68, respectively; P=0.02 vs. placebo, for both comparisons). The cumulative probability of disability progression (confirmed after 3 months) was 17.7% with 0.5 mg of fingolimod, 16.6% with 1.25 mg of fingolimod, and 24.1% with placebo. Both fingolimod doses were superior to placebo with regard to MRI-related measures (number of new or enlarged lesions on T2 -weighted images, gadolinium-enhancing lesions, and brain-volume loss; P<0.001 for all comparisons at 24 months). Causes of study discontinuation and adverse events related to fingolimod included bradycardia and atrioventricular conduction block at the time of fingolimod initiation, macular edema, elevated liver-enzyme levels, and mild hypertension.

Conclusions As compared with placebo, both doses of oral fingolimod improved the relapse rate, the risk of disability progression, and end points on MRI. These benefits will need to be weighed against possible long-term risks. (ClinicalTrials.gov number, NCT00289978 [ClinicalTrials.gov] .)

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Published at www.nejm.org January 20, 2010 (10.1056/NEJMoa0902533)

A Placebo-Controlled Trial of Oral Cladribine for Relapsing Multiple Sclerosis
Gavin Giovannoni, M.B., B.Ch., Ph.D., Giancarlo Comi, M.D., Stuart Cook, M.D., Kottil Rammohan, M.D., Peter Rieckmann, M.D., Per Soelberg S?rensen, M.D., D.M.Sc., Patrick Vermersch, M.D., Ph.D., Peter Chang, Ph.D., Anthony Hamlett, Ph.D., Bruno Musch, M.D., Ph.D., Steven J. Greenberg, M.D., for the CLARITY Study Group

ABSTRACT

Background Cladribine provides immunomodulation through selective targeting of lymphocyte subtypes. We report the results of a 96-week phase 3 trial of a short-course oral tablet therapy in patients with relapsing--remitting multiple sclerosis.

Methods We randomly assigned 1326 patients in an approximate 1:1:1 ratio to receive one of two cumulative doses of cladribine tablets (either 3.5 mg or 5.25 mg per kilogram of body weight) or matching placebo, given in two or four short courses for the first 48 weeks, then in two short courses starting at week 48 and week 52 (for a total of 8 to 20 days per year). The primary end point was the rate of relapse at 96 weeks.

Results Among patients who received cladribine tablets (either 3.5 mg or 5.25 mg per kilogram), there was a significantly lower annualized rate of relapse than in the placebo group (0.14 and 0.15, respectively, vs. 0.33; P<0.001 for both comparisons), a higher relapse-free rate (79.7% and 78.9%, respectively, vs. 60.9%; P<0.001 for both comparisons), a lower risk of 3-month sustained progression of disability (hazard ratio for the 3.5-mg group, 0.67; 95% confidence interval [CI], 0.48 to 0.93; P=0.02; and hazard ratio for the 5.25-mg group, 0.69; 95% CI, 0.49 to 0.96; P=0.03), and significant reductions in the brain lesion count on magnetic resonance imaging (MRI) (P<0.001 for all comparisons). Adverse events that were more frequent in the cladribine groups included lymphocytopenia (21.6% in the 3.5-mg group and 31.5% in the 5.25-mg group, vs. 1.8%) and herpes zoster (8 patients and 12 patients, respectively, vs. no patients).

Conclusions Treatment with cladribine tablets significantly reduced relapse rates, the risk of disability progression, and MRI measures of disease activity at 96 weeks. The benefits need to be weighed against the risks. (ClinicalTrials.gov number, NCT00213135 [ClinicalTrials.gov] .)

 

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多発性硬化症の経口治療薬/cladribine fingolimod 冬虫夏草 医師の一分/BIGLOBEウェブリブログ
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