Statin類藥物在多發性硬化症重整旗鼓
作者：Allison Gandey
出處：WebMD醫學新聞
October 14, 2009 (巴爾的摩) — Simvastatin這個由Merck藥廠率先以商品名Zocor行銷、被普遍使用的降血脂藥物，現在正被研發用於多發性硬化症；在美國神經科協會第134屆年會中，研究者發表指出，該藥物可針對多發性硬化症的自體反應細胞作用。
第一作者、北卡羅來納大學的Xin Zhang醫師在訪問中表示，Simvastatin抑制復發型多發性硬化症病患的Th17細胞分化。Th17細胞在此疾病發展中被認為扮演重要角色。
Zhang醫師的團隊進行的信號實驗認為，使用simvastatin進行前期治療可改變CD45RA+細胞進行Th17分化，並抑制干擾素調節因素。研究者認為，是在樹突細胞內藉由四異戊二烯化作用(geranylgeranylation)而達到此抑制。
Zhang醫師向Medscape Neurology表示，她的團隊向藥廠提及新的statin類藥物試驗的可能性。
Statins類藥物在多發性硬化症方面有時已經佔據頭條，但是許多人推測這個熱潮在「Atorvastatin (Lipitor) Therapy in Patients With Clinically Isolated Syndrome at Risk for Multiple Sclerosis (STAYCIS)」這項研究發表有害於atorvastatin的資料之後會衰退。
最近的歐洲多發性硬化症治療與研究委員會年會中，研究者描述一個因招募緩慢與納入問題而失敗的試驗。
【STAYCIS研究的問題】
這個18個月的研究是一個隨機、雙盲、安慰劑控制試驗，它探討80 mg atorvastatin (商品名Lipitor，Pfizer藥廠)用於延遲或降低臨床與磁振造影疾病活性的效果。
研究者聚焦在臨床獨立症狀以及磁振造影發現認為是多發性硬化症的病患。該試驗希望有152名病患，但是只招募到82人。
資深研究者、加州大學舊金山分校的Scott Zamvil醫師在9月的會議中向Medscape Neurology表示，我們的試驗強度不符合計畫的效應。我們招募的研究對象不足，事後證明，這個研究設計無法達到我們的初級終點，像這樣的第2期研究，應該區分磁振造影的終點。
研究者希望，以有良好安全紀錄的atorvastatin進行治療可以獲得免疫上的耐受性。不過，試驗沒有成功，儘管研究者從參與的14個中心納入82個病患，這個研究問題仍然無解。
會議的共同主持人、英國倫敦醫學與牙醫學院Barts細胞與分子科學研究中心的Gavin Giovannoni博士表示，很不幸地，這是一個倫理議題，強調了邏輯思考與完整考量的重要性。
訪問中，國立健康研究中心細胞免疫小組的代理組長Henry McFarland醫師表示同意。如果你開始一個研究，在倫理上有義務完整考量，且儘可能確保有適當的世代參與。
研究者皆宣告沒有相關財務關係。
美國神經科協會第134屆年會：壁報T22。發表於2009年10月13日。
Statins Making Comeback in Multiple Sclerosis
By Allison Gandey
Medscape Medical News
October 14, 2009 (Baltimore, Maryland) — Simvastatin, the popular lipid-lowering drug first marketed by Merck as Zocor, is now being investigated in multiple sclerosis. Presenting here at the 134th annual meeting of the American Neurological Association, researchers showed that the drug may target cells involved in the autoimmune response in multiple sclerosis.
"Simvastatin inhibits Th17 cell differentiation in patients with relapsing-remitting multiple sclerosis," lead investigator Xin Zhang, MD, from the University of North Carolina at Chapel Hill, said during an interview. Th17 cells are thought to play a critical role in disease development.
Dr. Zhang's team conducted signaling experiments suggesting that pretreatment with simvastatin altered CD45RA+ cells undergoing Th17 differentiation and inhibited the interferon regulatory factor. The researchers suggest that inhibition is taking place by geranylgeranylation in the dendritic cells.
Dr. Zhang told Medscape Neurology that her colleagues are talking to drug makers about the possibility for new statin trials.
Statins have been making headlines for some time in multiple sclerosis, but many speculated that enthusiasm would wane after Atorvastatin (Lipitor) Therapy in Patients With Clinically Isolated Syndrome at Risk for Multiple Sclerosis (STAYCIS) study investigators presented damaging atorvastatin data.
Presenting at the recent European Committee for Treatment and Research in Multiple Sclerosis annual meeting, researchers described a trial crippled by slow enrollment and recruitment problems.
The Problem with STAYCIS
The 18-month study was a randomized, double-blind, placebo-controlled trial. It explored the effect of 80 mg atorvastatin (Lipitor, Pfizer) in delaying or decreasing clinical and magnetic resonance imaging disease activity.
Investigators focused on patients with clinically isolated syndrome and magnetic resonance findings suggestive of multiple sclerosis. The trial design called for 152 patients, but only 82 were recruited.
"We were underpowered to detect the planned effect," senior investigator Scott Zamvil, MD, from the University of California–San Francisco, told Medscape Neurology at the September meeting. "We had a lack of enrollment, and in hindsight, it was highly unlikely that we were ever going to make our primary endpoint with this design," Dr. Zamvil said. "A phase 2 study like this probably should have had a separate magnetic resonance imaging endpoint."
This is very tragic.
Investigators had hoped that treatment with atorvastatin, known for having a good safety track record, would result in immunologic tolerance. However, the trial was unsuccessful, which means that despite the work of investigators from the 14 centers involved and the efforts of the 82 patients recruited, the study question has no answer.
"This is very tragic," said session cochair Gavin Giovannoni, PhD, from the Institute of Cell and Molecular Science at Barts and the London School of Medicine and Dentistry, in the United Kingdom. "This is an ethical issue and really highlights how important it is to consider logistics and think things through," Dr. Giovannoni said.
During an interview, Henry McFarland, MD, acting chief of the cellular immunology section of the National Institutes of Health, said he agrees, "If you start a study, you have an ethical obligation to see it through and do everything possible to ensure there is a sufficient cohort."
The researchers have disclosed no relevant financial relationships.
American Neurological Association 134th Annual Meeting: Poster T22. Presented October 13, 2009.
