美国加州大学圣地亚哥分校Joseph L. Witztum和加拿大蒙特利尔大学Daniel Gaudet研究组宣布，他们发现新药volanesorsen可有效降低家族性高乳糜微粒血症患者的甘油三酯水平。该项研究成果发表在2019年8月8日出版的《新英格兰医学杂志》上。

研究组进行了一项为期52周的3期双盲随机试验，以评估volanesorsen对66例家族性高乳糜血综合征患者的安全性和有效性。按照1:1的比例将患者随机分为两组，分别接受volanesorsen治疗或安慰剂。观察指标为空腹甘油三酯水平的百分比变化。治疗3个月后，volanesorsen组患者的平均血浆载脂蛋白C-III水平比治疗前下降了25.7 mg/dl，相当于下降了84%，而安慰剂组患者比治疗前增加了1.9 mg/dl，相当于上升了6.1%；volanesorsen组患者的平均甘油三酯水平下降了77%，安慰剂组患者却上升了18%，差异显著。安慰剂组中10%的患者和volanesorsen组中77%的患者甘油三酯水平降到了750 mg/dl以下。但volanesorsen组中有20例患者发生注射部位反应，15例患者发生血小板减少，安慰剂组中无一例患者发生不良反应。

据介绍，家族性高乳糜微粒血症是一种罕见的遗传性疾病，由脂蛋白脂肪酶失活引起，以乳糜微粒血症和反复发作的胰腺炎为特征。目前还没有有效的治疗方法。在此前一项针对三名家族性高乳糜微粒血综合征患者的开放标签研究中，反义介导抑制肝APOC3 mRNA的药物volanesorsen会造成血浆载脂蛋白C-III和甘油三酯水平下降。

附：英文原文

Title: Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome

Author: Joseph L. Witztum, M.D., Daniel Gaudet, M.D., Ph.D., Steven D. Freedman, M.D., Ph.D., Veronica J. Alexander, Ph.D., Andres Digenio, M.D., Ph.D., Karren R. Williams, Ph.D., Qingqing Yang, M.D., Steven G. Hughes, M.B., B.S., Richard S. Geary, Ph.D., Marcello Arca, M.D., Erik S.G. Stroes, M.D., Ph.D., Jean Bergeron, M.D., Handrean Soran, M.D., Fernando Civeira, M.D., Linda Hemphill, M.D., Sotirios Tsimikas, M.D., Dirk J. Blom, M.D., Ph.D., Louis O’Dea, M.D., Eric Bruckert, M.D.

Issue&Volume: Vol.381 No.6

Abstract:

BACKGROUND

Familial chylomicronemia syndrome is a rare genetic disorder that is caused by loss of lipoprotein lipase activity and characterized by chylomicronemia and recurrent episodes of pancreatitis. There are no effective therapies. In an open-label study of three patients with this syndrome, antisense-mediated inhibition of hepatic APOC3 mRNA with volanesorsen led to decreased plasma apolipoprotein C-III and triglyceride levels.

METHODS

We conducted a phase 3, double-blind, randomized 52-week trial to evaluate the safety and effectiveness of volanesorsen in 66 patients with familial chylomicronemia syndrome. Patients were randomly assigned, in a 1:1 ratio, to receive volanesorsen or placebo. The primary end point was the percentage change in fasting triglyceride levels from baseline to 3 months.

RESULTS

Patients receiving volanesorsen had a decrease in mean plasma apolipoprotein C-III levels from baseline of 25.7 mg per deciliter, corresponding to an 84% decrease at 3 months, whereas patients receiving placebo had an increase in mean plasma apolipoprotein C-III levels from baseline of 1.9 mg per deciliter, corresponding to a 6.1% increase (P<0.001). Patients receiving volanesorsen had a 77% decrease in mean triglyceride levels, corresponding to a mean decrease of 1712 mg per deciliter (19.3 mmol per liter) (95% confidence interval [CI], 1330 to 2094 mg per deciliter [15.0 to 23.6 mmol per liter]), whereas patients receiving placebo had an 18% increase in mean triglyceride levels, corresponding to an increase of 92.0 mg per deciliter (1.0 mmol per liter) (95% CI, −301.0 to 486 mg per deciliter [–3.4 to 5.5 mmol per liter]) (P<0.001). At 3 months, 77% of the patients in the volanesorsen group, as compared with 10% of patients in the placebo group, had triglyceride levels of less than 750 mg per deciliter (8.5 mmol per liter). A total of 20 of 33 patients who received volanesorsen had injection-site reactions, whereas none of the patients who received placebo had such reactions. No patients in the placebo group had platelet counts below 100,000 per microliter, whereas 15 of 33 patients in the volanesorsen group had such levels, including 2 who had levels below 25,000 per microliter. No patient had platelet counts below 50,000 per microliter after enhanced platelet-monitoring began.

CONCLUSIONS

Volanesorsen lowered triglyceride levels to less than 750 mg per deciliter in 77% of patients with familial chylomicronemia syndrome. Thrombocytopenia and injection-site reactions were common adverse events.

DOI: 10.1056/NEJMoa1715944

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1715944