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asciminib治疗新诊断慢性髓系白血病试验
Asciminib in Newly Diagnosed Chronic Myeloid Leukemia
背景
新诊断慢性髓系白血病（CML）患者需要高效且安全的长期疗法。asciminib是特异性靶向ABL肉豆蔻酰口袋的BCR::ABL1抑制剂，与目前的一线ATP竞争性酪氨酸激酶抑制剂（TKI）相比，asciminib可能具有更好的疗效和安全性，副作用也更少。
Patients with newly diagnosed chronic myeloid leukemia (CML) need long-term therapy with high efficacy and safety. Asciminib, a BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket, may offer better efficacy and safety and fewer side effects than currently available frontline ATP-competitive tyrosine kinase inhibitors (TKIs)
方法
在一项3期试验中，新诊断CML患者以1:1比例被随机分配接受asciminib（80 mg，每日一次）或研究者选择的TKI治疗。随机分组按照欧洲治疗与结局研究（European Treatment and Outcome Study）长期生存评分类别（低危、中危或高危）和研究者在随机分组前选择的TKI（包括伊马替尼和第二代TKI）进行分层。主要终点是第48周时达到主要分子学缓解（定义为根据国际量表[IS，International Scale]，BCR::ABL1转录物水平≤0.1%），此项终点在asciminib组与研究者选择的TKI组之间进行比较，并且在随机分组前选择的伊马替尼分层中，在asciminib组与研究者选择的TKI组之间进行比较。
In a phase 3 trial, patients with newly diagnosed CML were randomly assigned in a 1:1 ratio to receive either asciminib (80 mg once daily) or an investigator-selected TKI, with randomization stratified by European Treatment and Outcome Study long-term survival score category (low, intermediate, or high risk) and by TKI selected by investigators before randomization (including imatinib and second-generation TKIs). The primary end points were major molecular response (defined as BCR::ABL1 transcript levels ≤0.1% on the International Scale [IS]) at week 48, for comparisons between asciminib and investigator-selected TKIs and between asciminib and investigator-selected TKIs in the prerandomization-selected imatinib stratum.
结果
共计201例患者被分配接受asciminib，204例患者被分配接受研究者选择的TKI。asciminib组的中位随访时间为16.3个月，研究者选择的TKI组为15.7个月。第48周时，asciminib组67.7%的患者达到主要分子学缓解，而研究者选择的TKI组为49.0%（差异，18.9个百分点；95%置信区间[CI]，9.6~28.2；校正后双侧P<0.001），在伊马替尼分层中，asciminib组69.3%的患者达到主要分子学缓解，而伊马替尼组为40.2%（差异，29.6个百分点；95% CI，16.9~42.2；校正后双侧P<0.001）。在第二代TKI分层中，第48周时达到主要分子学缓解的患者比例为asciminib组66.0%，TKI组57.8%（差异，8.2个百分点；95% CI，－5.1~21.5）。在asciminib（分别为38.0%和4.5%）组中，3级或更高级别不良事件以及导致停药的不良事件发生率低于伊马替尼组（分别为44.4%和11.1%）和第二代TKI组（分别为54.9%和9.8%）。
Result
A total of 201 patients were assigned to receive asciminib and 204 to receive investigator-selected TKIs. The median follow-up was 16.3 months in the asciminib group and 15.7 months in the investigator-selected TKI group. A major molecular response at week 48 occurred in 67.7% of patients in the asciminib group, as compared with 49.0% in the investigator-selected TKI group (difference, 18.9 percentage points; 95% confidence interval [CI], 9.6 to 28.2; adjusted two-sided P<0.001]), and in 69.3% of patients in the asciminib group as compared with 40.2% in the imatinib group within the imatinib stratum (difference, 29.6 percentage points; 95% CI, 16.9 to 42.2; adjusted two-sided P<0.001). The percentage of patients with a major molecular response at week 48 was 66.0% with asciminib and 57.8% with TKIs in the second-generation TKI stratum (difference, 8.2 percentage points; 95% CI, −5.1 to 21.5). Adverse events of grade 3 or higher and events leading to discontinuation of the trial regimen were less frequent with asciminib (38.0% and 4.5%, respectively) than with imatinib (44.4% and 11.1%) and second-generation TKIs (54.9% and 9.8%).
结论
在此项比较asciminib与研究者选择的TKI及伊马替尼的试验中，asciminib对新诊断慢性期CML患者具有更好疗效和良好安全性。asciminib和第二代TKI的直接比较并不是本试验的主要目的。（由诺华公司资助；ASC4FIRST在ClinicalTrials.gov注册号为NCT04971226）。
Conclusions
In this trial comparing asciminib with investigator-selected TKIs and imatinib, asciminib showed superior efficacy and a favorable safety profile in patients with newly diagnosed chronic-phase CML. Direct comparison between asciminib and second-generation TKIs was not a primary objective. (Funded by Novartis; ASC4FIRST ClinicalTrials.gov number, NCT04971226).
靶向APOC3的RNA干扰剂plozasiran治疗混合型高脂血症
Plozasiran, an RNA Interference Agent Targeting APOC3, for Mixed Hyperlipidemia
背景
混合型高脂血症患者的非高密度脂蛋白（HDL）胆固醇水平升高，因此面临患动脉粥样硬化性心血管疾病的风险，而引起非HDL胆固醇水平升高的原因是富含甘油三酯的脂蛋白中的残余胆固醇。通过载脂蛋白C3（APOC3）介导的对脂蛋白脂肪酶的抑制作用，富含甘油三酯的脂蛋白的代谢和清除受到下调。
我们开展了一项为期48周的2b期双盲、随机、安慰剂对照试验，目的是评估靶向肝细胞的APOC3小干扰RNA plozasiran对混合型高脂血症患者（即甘油三酯水平为150~499 mg/dL，并且低密度脂蛋白[LDL]胆固醇水平≥70 mg/dL或非HDL胆固醇水平≥100 mg/dL）的安全性和疗效。在4个队列的每一个中均以3:1比例分配参与者接受plozasiran或安慰剂治疗。在前3个队列中，参与者分别在第1天和第12周（季度给药）皮下注射plozasiran（10 mg、25 mg或50 mg）或安慰剂。在第4个队列中，参与者在第1天和第24周（半年给药）接受50 mg plozasiran或安慰剂。将接受安慰剂治疗参与者的数据汇总。主要终点是第24周时空腹甘油三酯水平的变化百分比。
Methods
We carried out a 48-week, phase 2b, double-blind, randomized, placebo-controlled trial evaluating the safety and efficacy of plozasiran, a hepatocyte-targeted APOC3 small interfering RNA, in patients with mixed hyperlipidemia (i.e., a triglyceride level of 150 to 499 mg per deciliter and either a low-density lipoprotein [LDL] cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). The participants were assigned in a 3:1 ratio to receive plozasiran or placebo within each of four cohorts. In the first three cohorts, the participants received a subcutaneous injection of plozasiran (10 mg, 25 mg, or 50 mg) or placebo on day 1 and at week 12 (quarterly doses). In the fourth cohort, participants received 50 mg of plozasiran or placebo on day 1 and at week 24 (half-yearly dose). The data from the participants who received placebo were pooled. The primary end point was the percent change in fasting triglyceride level at week 24.
共计353名参与者接受随机分组。第24周时，接受plozasiran治疗参与者的空腹甘油三酯水平显著降低，相对于基线的最小二乘平均变化百分比与安慰剂的差异如下：10 mg季度给药为－49.8个百分点（95%置信区间[CI]，－59.0~－40.6），25 mg季度给药为－56.0个百分点（95% CI，－65.1~－46.8），50 mg季度给药为－62.4个百分点（95% CI，－71.5~－53.2），50 mg半年给药为－44.2个百分点（95% CI，－53.4~－35.0）（所有比较的P<0.001）。血糖控制情况恶化的参与者比例如下：安慰剂为10%，10 mg季度给药为12%，25 mg季度给药为7%，50 mg季度给药为20%，50 mg半年给药为21%。
Result
A total of 353 participants underwent randomization. At week 24, significant reductions in the fasting triglyceride level were observed with plozasiran, with differences, as compared with placebo, in the least-squares mean percent change from baseline of −49.8 percentage points (95% confidence interval [CI], −59.0 to −40.6) with the 10-mg-quarterly dose, −56.0 percentage points (95% CI, −65.1 to −46.8) with the 25-mg-quarterly dose, −62.4 percentage points (95% CI, −71.5 to −53.2) with the 50-mg-quarterly dose, and −44.2 percentage points (95% CI, −53.4 to −35.0) with the 50-mg-half-yearly dose (P<0.001 for all comparisons). Worsening glycemic control was observed in 10% of the participants receiving placebo, 12% of those receiving the 10-mg-quarterly dose, 7% of those receiving the 25-mg-quarterly dose, 20% of those receiving the 50-mg-quarterly dose, and 21% of those receiving the 50-mg-half-yearly dose.
结论
在此项对混合型高脂血症患者开展的随机对照试验中，与安慰剂相比，plozasiran显著降低了第24周的甘油三酯水平。有必要开展评估临床结局的试验。（由Arrowhead Pharmaceuticals资助；MUIR在ClinicalTrials.gov注册号为NCT04998201）。
靶向ANGPTL3的RNAi疗法zodasiran治疗混合型高脂血症
Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia
背景
血管生成素样蛋白3（ANGPTL3）可抑制脂蛋白和内皮脂肪酶，以及肝脏对富含甘油三酯的脂蛋白残粒的摄取。与ANGPTL3失活变异的非携带者相比，携带者的甘油三酯、低密度脂蛋白（LDL）胆固醇、高密度脂蛋白（HDL）胆固醇和非HDL胆固醇水平较低，患动脉粥样硬化性心血管疾病的风险也较低。zodasiran是靶向肝脏内ANGPTL3表达的RNA干扰（RNAi）疗法。
我们开展了一项双盲、安慰剂对照、剂量范围探索2b期试验，目的是评估zodasiran对混合型高脂血症（空腹甘油三酯水平150~499 mg/dL，LDL胆固醇水平≥70 mg/dL或非HDL胆固醇水平≥100 mg/dL）成人患者的安全性和疗效。以3:1比例将符合标准患者随机分组，分别在第1天和第12周接受zodasiran（50、100或200 mg）或安慰剂皮下注射，并随访至第36周。主要终点是甘油三酯水平从基线到第24周的变化百分比。
Methods
We conducted a double-blind, placebo-controlled, dose-ranging phase 2b trial to evaluate the safety and efficacy of zodasiran in adults with mixed hyperlipidemia (fasting triglyceride level of 150 to 499 mg per deciliter and either an LDL cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). Eligible patients were randomly assigned in a 3:1 ratio to receive subcutaneous injections of zodasiran (50, 100, or 200 mg) or placebo on day 1 and week 12 and were followed through week 36. The primary end point was the percent change in the triglyceride level from baseline to week 24.
共计204例患者接受随机分组。第24周时，zodasiran组ANGPTL3水平相对于基线发生大幅、剂量依赖性平均下降（与安慰剂相比，变化幅度差异，50 mg组为－54个百分点，100 mg组为－70个百分点，200 mg组为－74个百分点），甘油三酯水平也出现剂量依赖性显著下降（与安慰剂相比，变化幅度差异，分别为－51个百分点、－57个百分点和－63个百分点）（所有比较的P<0.001）。相对于基线的变化幅度与安慰剂组之间的其他差异包括：非HDL胆固醇水平，50 mg组－29个百分点，100 mg组－29个百分点，200 mg组－36个百分点；载脂蛋白B水平，分别为－19个百分点、－15个百分点和－22个百分点；LDL胆固醇水平，分别为－16个百分点、－14个百分点和－20个百分点。我们观察到，在接受最大剂量zodasiran治疗的原有糖尿病患者中，糖化血红蛋白水平会出现一过性升高。
Result
A total of 204 patients underwent randomization. At week 24, substantial mean dose-dependent decreases from baseline in ANGPTL3 levels were observed with zodasiran (difference in change vs. placebo, −54 percentage points with 50 mg, −70 percentage points with 100 mg, and −74 percentage points with 200 mg), and significant dose-dependent decreases in triglyceride levels were observed (difference in change vs. placebo, −51 percentage points, −57 percentage points, and −63 percentage points, respectively) (P<0.001 for all comparisons). Other differences in change from baseline as compared with placebo included the following: for non-HDL cholesterol level, −29 percentage points with 50 mg, −29 percentage points with 100 mg, and −36 percentage points with 200 mg; for apolipoprotein B level, −19 percentage points, −15 percentage points, and −22 percentage points, respectively; and for LDL cholesterol level, −16 percentage points, −14 percentage points, and −20 percentage points, respectively. We observed a transient elevation in glycated hemoglobin levels in patients with preexisting diabetes who received the highest dose of zodasiran.
结论
对于混合型高脂血症患者，zodasiran治疗与第24周的甘油三酯水平显著下降相关。（由Arrowhead Pharmaceuticals资助；ARCHES-2在ClinicalTrials.gov注册号为NCT04832971）
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