Eprodisate Disodium降低了淀粉样变性病之肾脏功能减退


  July 19, 2006 (苏格兰) — 一项国际性第二期随机控制试验发现,eprodisate disodium (NC-503; Neurochem)在降低淀粉样变性病(AA)之肾脏功能减退是安全且有效的。
  
  英国伦敦Royal Free大学医学部的Helen Lachmann医师向与会听众表示,这是首次发展出对此类病患有用的药物;Eprodisate disodium是此类antiamyloid制剂的第一个药物。
  
  该篇摘要被评选为第43届欧洲肾脏协会 (ERA)–欧洲透析及移植协会(EDTA)会议的八篇佳作之一,且是11篇年轻作者所发表的最佳摘要之一。
  
  【罕见却致命的疾病】
  淀粉样变性病相对少见但却有并发慢性发炎的致命潜在危险,此疾病的特征是淀粉样蛋白沉积导致组织损伤,特别是肾脏,包括肠和肝脏;肾病症候群和肾丝球速率(GFR)减低在临床占重要地位,在每一仟个肾脏切片中约有三个 AA 沉积案例。
  
  目前对淀粉样变性病所仅有的治疗是控制发炎,没有特定药物可供治疗;此一多中心研究目标在评估eprodisate disodium之安全性和有效性,此药是一种以特定的淀粉样蛋白为标靶的药物,用于此症且并有肾功能异常之病患。
  
  该研究是一个包括13国23中心之大型协力研究的一部分,共筛检261位病患,纳入183位于此研究;符合的规范包括大于18岁、切片证明淀粉样变性病、且肾功能不佳定义为每天超过1 g蛋白质或CrCl小于60 mL/min;末期肾病变者则不纳入。
  
  病患随机分组接受安慰剂(94人)或eprodisate disodium (89人) 、为期24个月;初级试验终点是一个综合评估,以确定肾功能有无更差 (如,CrCl减少 50%、血清 Cr加倍、病情进展为洗肾、或死亡),或为改善 (如,CrCl增加 50% ),或者是稳定。
  
  本研究之治疗组共有 63位病患、安慰剂祖有61人完成试验;两组之性别、年纪、蛋白尿 (平均 4.1 g/day)、以及部分肾脏症状(38% vs 42%)等资料均相符。
  
  【鼓舞的结果】
  相较于安慰剂组,接受eprodisate disodium者有42%肾衰竭或死亡的风险降低(95% 信心区间、 37% – 93%; P = .025),治疗组的病患平均有两倍之血清肌酸酐和增加50%的CrCl;研究作者结论认为, NC-503 有临床意义且对肾脏疾病病程有显著好处。
  
  该药的安全资料和安慰剂相若,严重的和不严重的不良反应有相似的发生率(严重的36% vs 42%、不严重的98% vs 93%)。
  
  24 个月之后,110位病患同意参加每个人皆服用eprodisate disodium的延长研究,原为安慰剂组转为接受此药者之三年肾功能减退率没有如以外插法所预测的那么高,Lachmann医师认为这是令人鼓舞的。
  
  Eprodisate disodium是第一个特定的抗淀粉样蛋白药物,她总结指出,在两年的随机安慰剂控制试验以及一个开放卷标延伸试验中均对淀粉样变性病有好处;Lachmann医师表示,此活性药物显出可降低肾脏事件风险、避免终将发生的肾脏病变,对对任何原因导致的死亡率则无显著降低。

Eprodisate Disodium Reduces Re

By Marlene Busko
Medscape Medical News

July 19, 2006 (Glasgow, Scotland) — An international phase 2 randomized controlled trial found that eprodisate disodium (NC-503; Neurochem) is safe and effective in lessening renal decline in patients who have amyloid A (AA) amyloidosis.

"For the first time, there has been development of a drug that is helpful [for these patients]," Helen Lachmann, MD, from the Royal Free and University College Medical School, London, United Kingdom, told meeting attendees. "Eprodisate disodium is the first member of a new class of antiamyloid agents."

The abstract was judged to be one of the 8 best of the 43rd European Renal Association (ERA)–European Dialysis and Transplant Association (EDTA) meeting here, and one of the 11 best abstracts presented by a young author.

Rare, Life-Threatening Disease

AA amyloidosis is a relatively rare but potentially life-threatening complication of chronic inflammatory conditions. The disease is characterized by amyloid deposits that cause tissue damage in the kidney especially, but also in the gut and liver. Nephrotic syndrome and decline of glomerular filtration rate (GFR) dominates the clinical picture. AA deposits are found in about 3 per 1000 renal biopsies.

At present, the only treatment for AA amyloidosis centers on ways to control the inflammation, as there is no specific drug approved to treat it. This multicenter trial aimed to evaluate the safety and efficacy of eprodisate disodium, an agent specifically targeting amyloid, in patients with this disease presenting with renal involvement.

The study was part of a large collaborative effort involving 23 centers in 13 countries. A total of 261 patients were screened, and 183 entered the study. Eligibility criteria included age older than 18 years, biopsy-proven AA amyloidosis, and renal dysfunction defined as more than 1 g protein per day or creatinine clearance (CrCl) of less than 60 mL/min. Patients with end-stage renal disease were excluded.

Patients were randomized to placebo (n = 94) or to eprodisate disodium (n = 89) for 24 months. The primary study end point was a composite assessment to determine whether renal function had worsened (ie, showed a 50% decrease in CrCl, doubling of serum Cr, progression to dialysis, or death), improved (ie, showed a 50% increase in CrCl), or remained stable.

A total of 63 patients in the treated group and 61 in the placebo group completed the study. The groups were well matched for sex, age, proteinuria (mean, 4.1 g/day), and proportion with nephrotic syndrome (38% vs 42%).

"Encouraging" Results

Compared with patients in the placebo group, those who received eprodisate disodium had a 42% reduction in risk of renal decline or death (95% confidence interval, 37% – 93%; P = .025). The treated patients had, on average, a longer time to doubling serum creatinine and a longer time to a 50% decrease in CrCl. "NC-503 had clinically meaningful and statistically significant beneficial effects on renal disease progression," the study authors summarized.

The safety profile of the drug was comparable to that of placebo, with similar incidences of serious and nonserious adverse events (36% vs 42% and 98% vs 93%, respectively).

After 24 months, 110 patients agreed to enter an extended study in which everyone received eprodisate disodium. When patients in the placebo group were converted to the active drug, their rate of decline in renal function at 3 years was not as great as predicted by extrapolating the rate they showed while receiving placebo. "This is encouraging," said Dr. Lachmann.

"Eprodisate disodium, the first specific anti-amyloid drug, has demonstrated renal benefits in AA amyloidosis in both a 2-year randomized, placebo-controlled trial and in an open-label extension study," she summarized. "The active drug demonstrates a reduction in risk of renal events and in time to renal events and a nonsignificant reduction in all-cause mortality," Dr. Lachmann concluded.

43rd ERA-EDTA Meeting: Abstract MO019. Presented July 17, 2006.

    
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