Volanesorsen
目录号 : GC65493
Volanesorsen是一种反义寡核苷酸，靶向载脂蛋白 C-III (APOC3) mRNA，用于家族性乳糜酶血症综合征的相关研究。
Cas No.:915430-78-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >94.00%
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Volanesorsen is an antisense oligonucleotide thay targes Apolipoprotein C-III (APOC3) mRNA. Volanesorsen is used for the study of familial chylomicronemia syndrome.
[1]. Graham MJ, Lee RG, Bell TA 3rd, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res. 2013;112(11):1479-1490. [2]. Gaudet D, Brisson D, Tremblay K, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014;371(23):2200-2206.
| Cas No. | 915430-78-3 | SDF | Download SDF |
| 分子式 | 分子量 | 7165 | |
| 溶解度 | H2O : 50 mg/mL (6.98 mM; Need ultrasonic) | 储存条件 | -20°C, away from moisture |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 0.1396 mL | 0.6978 mL | 1.3957 mL |
| 5 mM | 0.0279 mL | 0.1396 mL | 0.2791 mL |
| 10 mM | 0.014 mL | 0.0698 mL | 0.1396 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome
N Engl J Med 2019 Aug 8;381(6):531-542.PMID:31390500DOI:10.1056/NEJMoa1715944.
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. (Funded by Ionis Pharmaceuticals and Akcea Therapeutics; APPROACH Clinical Trials.gov number, NCT02211209.).
Volanesorsen to treat severe hypertriglyceridaemia: A pooled analysis of randomized controlled trials
Eur J Clin Invest 2022 Nov;52(11):e13841.PMID:35851450DOI:10.1111/eci.13841.
Background: Patients with severe hypertriglyceridaemia (sHTG) are often refractory to lipid-lowering therapy. Apolipoprotein (Apo) CIII inhibition could be promising to treat subjects with sHTG. The antisense oligonucleotide against APOC3 mRNA Volanesorsen was recently introduced to treat sHTG. We performed a systematic review and meta-analysis of RCTs on the efficacy and safety of Volanesorsen as compared to placebo treatment in patients with severe HTG. Methods: Studies were systematically searched in the PubMed, Web of Science and Scopus databases according to PRISMA guidelines. The last search was performed on 7 February 2022. Results: Four studies showed significant reduction in TG after 3 months of treatment with Volanesorsen as compared with placebo (MD: -73.9%; 95%CI: -93.5%, -54.2; p < .001 I2 = 89.05%; p < .001); VLDL-C level (MD: -71.0%; 95%CI: -76.6%, -65.4%; p < .001 I2 = 94.1%; p < .001); Apo-B48 level (MD: -69.03%; 95%CI: -98.59.4%, -39.47%; p < .001, I2 = 93.51%; p < .001) and Apo-CIII level (MD: -80.0%; 95%CI: -97.5%, -62.5; p < .001 I2 = 94.1%; p < .001) with an increase in HDL-C level (MD: +45.92%, 95%CI: +37.24%, +54.60%; p < .001 I2 = 94.34%; p < .001) and in LDL-C level (MD: +68.6%, 95%CI: +7.0%, +130.1%; p < .001 I2 = 96.18%; p < .001) without a significant elevation of Apo-B100 level (MD: +4.58%, 95%CI: -5.64%, +14.79%; p = .380 I2 = 95.09%; p < .001) in 139 Volanesorsen patients as compared to 100 placebo-treated controls. Most of adverse events were mild and related to local injection site reactions. Conclusions: In patients with severe HTG, Volanesorsen is associated with a significant reduction in TG, VLDL-C, Apo-B48 and non-HDL-C and increment of HDL-C as compared to placebo. Documented efficacy is accompanied by an acceptable safety profile.
Volanesorsen for treatment of familial chylomicronemia syndrome
Expert Rev Cardiovasc Ther 2021 Aug;19(8):685-693.PMID:34261380DOI:10.1080/14779072.2021.1955348.
Introduction: Familial chylomicronemia syndrome (FCS) is a rare subtype of severe hypertriglyceridemia that affects ~1 in 100, 000 to 1,000,000 individuals. The major risk to health is acute pancreatitis. FCS is defined by biallelic loss-of-function mutations in one of five canonical genes that encode proteins critical to lipolysis of large triglyceride-rich lipoprotein particles. Unlike the vast majority of patients with severe hypertriglyceridemia, FCS patients lack any lipolytic capacity and are thus resistant to standard medications. Areas covered: This review focuses on a mechanism that effectively reduces elevated triglyceride levels in FCS, namely interference of synthesis of apolipoprotein (apo) C-III. Volanesorsen is an antisense RNA drug administered subcutaneously that knocks down apo C-III, resulting in dramatic reductions in triglyceride levels both in FCS patients and in the wider population of subjects with severe hypertriglyceridemia. Expert opinion: Volanesorsen is a highly effective treatment to reduce elevated triglycerides in FCS patients, providing proof-of-concept of the validity of targeting apo C-III. However, off target effects of Volanesorsen, including thrombocytopenia, may ultimately limit its use. Nonetheless, building on the knowledge derived from the Volanesorsen experience, there is intensified interest in promising newer agents that also target apo C-III but have technical modifications that limit potential off target adverse effects.
Volanesorsen: A New Era in the Treatment of Severe Hypertriglyceridemia
J Clin Med 2022 Feb 13;11(4):982.PMID:35207255DOI:10.3390/jcm11040982.
Familial chylomicronemia syndrome (FCS) is a rare inherited disease, mainly due to lipoprotein lipase (LPL) gene mutations, leading to lipid abnormalities. Volanesorsen, a second-generation 2'-O-methoxyethyl (2'-MOE) chimeric antisense therapeutic oligonucleotide, can decrease plasma apolipoprotein C3 and triglycerides (TG) levels through LPL-independent pathways. The European Medicines Agency has approved Volanesorsen as an adjunct to diet in adult FCS patients with an inadequate response to TG-lowering therapy. Areas covered: Available clinical data on Volanesorsen efficacy and safety are presented. Furthermore, we discuss the yearly treatment with Volanesorsen of a 21-year-old female FCS patient with LPL mutation. Volanesorsen was well-tolerated and decreased patient's TG levels (from >5000 mg/dL (56 mmol/L) to 350-500 mg/dL (4-5.6 mmol/L)) at 12 months. Lipoprotein apheresis (LA) was stopped and there were no episodes of pancreatitis or abdominal pain. Expert opinion: Severe hypertriglyceridemia can potentially be fatal. Until recently, there was no specific treatment for FCS, apart from hypotriglyceridemic diet, fibrates, omega-3 fatty acids, and LA sessions. Therefore, Volanesorsen represents a promising therapeutic solution for these patients. The main side effect of Volanesorsen therapy is thrombocytopenia, which should be monitored and treated accordingly. Increasing evidence will further elucidate the clinical implications of Volanesorsen use in daily practice.
Efficacy and safety of Volanesorsen in patients with multifactorial chylomicronaemia (COMPASS): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial
Lancet Diabetes Endocrinol 2021 May;9(5):264-275.PMID:33798466DOI:10.1016/S2213-8587(21)00046-2.
Background: Volanesorsen is an antisense oligonucleotide that targets hepatic apolipoprotein C-III synthesis and reduces plasma triglyceride concentration. The aim of this study was to explore the safety and efficacy of Volanesorsen in patients with multifactorial chylomicronaemia syndrome. Methods: The COMPASS trial was a randomised, placebo-controlled, double-blind, phase 3 study done at 38 international clinical sites in Canada, France, Germany, the Netherlands, UK, and USA. Eligible patients were aged 18 years or older with multifactorial severe hypertriglyceridaemia or familial chylomicronaemia syndrome, who had a BMI of 45 kg/m2 or less and fasting plasma triglyceride of 500 mg/dL or higher. Patients were randomly assigned (2:1) with an interactive response system using an allocation sequence and permuted block randomisation to receive subcutaneous Volanesorsen (300 mg) or a matched volume of placebo (1·5 mL) once a week for 26 weeks. After 13 weeks of treatment, dosing was changed to 300 mg of Volanesorsen or placebo every 2 weeks for all patients, except those who had completed 5 months or more of treatment as of May 27, 2016. Participants, investigators, sponsor personnel, and clinical research staff were all masked to the treatment assignments. The primary outcome was percentage change from baseline to 3 months in fasting triglyceride in the full analysis set (all patients who were randomly assigned and received at least one dose of study drug and had a baseline fasting triglyceride assessment). This trial is registered with ClinicalTrials.gov, NCT02300233 (completed). Findings: Between Feb 5, 2015, and Jan 24, 2017, 408 patients were screened for eligibility. 294 were excluded and 114 randomly assigned to receive either Volanesorsen (n=76) or placebo (n=38). One patient in the Volanesorsen group discontinued before receiving the study drug. The total number of dropouts was 28 (four in the placebo group and 24 in the treatment group). Volanesorsen reduced mean plasma triglyceride concentration by 71·2% (95% CI -79·3 to -63·2) from baseline to 3 months compared with 0·9% (-13·9 to 12·2) in the placebo group (p<0·0001), representing a mean absolute reduction of fasting plasma triglycerides of 869 mg/dL (95% CI -1018 to -720; 9·82 mmol/L [-11·51 to -8·14]) in Volanesorsen compared with an increase in placebo of 74 mg/dL (-138 to 285; 0·83 mmol/L [-1·56 to 3·22]; p<0·0001). In the key safety analysis, five adjudicated events of acute pancreatitis occurred during the study treatment period, all in three of 38 patients in the placebo group. The most common adverse events were related to tolerability and included injection-site reactions (average of 24% of all Volanesorsen injections vs 0·2% of placebo injections), which were all mild or moderate. One participant in the Volanesorsen group had a platelet count reduction to less than 50 000 per μL and one patient had serum sickness, both of which were regarded as serious adverse events. Interpretation: Volanesorsen significantly reduced triglyceride concentrations in patients with multifactorial chlyomicronaemia and might reduce acute pancreatitis events in these patients. Funding: Ionis Pharmaceuticals and Akcea Therapeutics.