■脂蛋白(a)(Lp[a])与动脉粥样硬化疾病和主动脉狭窄有关。Lp(a)通过载脂蛋白(a)(apo[a])和apoB100之间的键合形成。Muvalaplin是一种口服小分子,通过阻断apo(a)-apoB100相互作用同时避免与同源蛋白相互作用来抑制Lp(a)形成,纤溶酶原.
■为了确定安全性,耐受性,药代动力学,和muvalaplin的药效学作用。
■第一阶段随机化,双盲,平行设计研究纳入了荷兰1个研究点的114名参与者(55人分配到单次递增剂量组;59人分配到多次递增剂量组).
■单次递增剂量治疗评估了任何Lp(a)水平的健康参与者服用1mg至800mg的单剂量muvalaplin或安慰剂的效果。多次递增剂量治疗评估了Lp(a)水平为30mg/dL或更高的患者每日服用muvalaplin(30mg至800mg)或安慰剂14天的效果。
■结果包括安全性,耐受性,药代动力学,和探索性药效学生物标志物。
■在114个随机分组(单剂量递增组55个:平均[SD]年龄,29[10]年,35名女性[64%],2美洲印第安人或阿拉斯加原住民[4%],50白色[91%],3个多种族[5%];多个递增剂量组59个:平均[SD]年龄32[15]岁;34名女性[58%];3名美洲印第安人或阿拉斯加原住民[5%],6黑色[10%],47白色[80%],3多种族[5%]),105完成了审判。Muvalaplin与耐受性问题或临床上显著的不良反应无关。口服剂量30mg至800mg持续14天导致muvalaplin血浆浓度增加,半衰期为70至414小时。Muvalaplin在第一次给药后24小时内降低了Lp(a)血浆水平,重复给药Lp(a)进一步降低。安慰剂调整后的最大Lp(a)降低为63%至65%,导致93%的参与者的Lp(a)血浆水平低于50mg/dL,在每日100毫克或更多的剂量下具有类似的效果。未观察到纤溶酶原水平或活性的临床显着变化。
■穆瓦拉普林,Lp(a)形成的选择性小分子抑制剂,与耐受性无关,每日给药后Lp(a)水平降低至65%,持续14天。将需要更长和更大的试验来进一步评估安全性,耐受性,和muvalaplin对Lp(a)水平和心血管结局的影响。
■ClinicalTrials.gov标识符:NCT04472676。
Lipoprotein(a) (Lp[a]) is associated with atherosclerotic disease and aortic stenosis. Lp(a) forms by bonding between apolipoprotein(a) (apo[a]) and apo B100. Muvalaplin is an orally administered small molecule that inhibits Lp(a) formation by blocking the apo(a)-apo B100 interaction while avoiding interaction with a homologous protein, plasminogen.
To determine the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of muvalaplin.
This phase 1 randomized, double-blind, parallel-design study enrolled 114 participants (55 assigned to a single-ascending dose; 59 assigned to a multiple-ascending dose group) at 1 site in the Netherlands.
The single ascending dose treatment evaluated the effect of a single dose of muvalaplin ranging from 1 mg to 800 mg or placebo taken by healthy participants with any Lp(a) level. The multiple ascending dose treatment evaluated the effect of taking daily doses of muvalaplin (30 mg to 800 mg) or placebo for 14 days in patients with Lp(a) levels of 30 mg/dL or higher.
Outcomes included safety, tolerability, pharmacokinetics, and exploratory pharmacodynamic biomarkers.
Among 114 randomized (55 in the single ascending dose group: mean [SD] age, 29 [10] years, 35 females [64%], 2 American Indian or Alaska Native [4%], 50 White [91%], 3 multiracial [5%]; 59 in the multiple ascending dose group: mean [SD] age 32 [15] years; 34 females [58%]; 3 American Indian or Alaska Native [5%], 6 Black [10%], 47 White [80%], 3 multiracial [5%]), 105 completed the trial. Muvalaplin was not associated with tolerability concerns or clinically significant adverse effects. Oral doses of 30 mg to 800 mg for 14 days resulted in increasing muvalaplin plasma concentrations and half-life ranging from 70 to 414 hours. Muvalaplin lowered Lp(a) plasma levels within 24 hours after the first dose, with further Lp(a) reduction on repeated dosing. Maximum placebo-adjusted Lp(a) reduction was 63% to 65%, resulting in Lp(a) plasma levels less than 50 mg/dL in 93% of participants, with similar effects at daily doses of 100 mg or more. No clinically significant changes in plasminogen levels or activity were observed.
Muvalaplin, a selective small molecule inhibitor of Lp(a) formation, was not associated with tolerability concerns and lowered Lp(a) levels up to 65% following daily administration for 14 days. Longer and larger trials will be required to further evaluate safety, tolerability, and effect of muvalaplin on Lp(a) levels and cardiovascular outcomes.
ClinicalTrials.gov Identifier: NCT04472676.