Background

Currently available injectable drugs that target proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce serum LDL cholesterol and improve cardiovascular outcomes. This phase 2 study assessed NNC0385-0434, an oral PCSK9 inhibitor, in individuals receiving oral lipid-lowering therapy.

Methods

In this randomised, double-blind, placebo-controlled and active-controlled trial, 42 research sites across seven countries (Belgium, Germany, Greece, Japan, the Netherlands, Poland, and the USA) recruited individuals with established atherosclerotic cardiovascular disease (aged ≥40 years) or at high risk of atherosclerotic cardiovascular disease (aged >50 years), who had LDL cholesterol concentration of at least 1·8 mmol/L and were receiving maximum tolerated statins and stable lipid-lowering therapy. The study randomly allocated participants (3:1) with an interactive web response system to receive either NNC0385-0434 (15 mg, 40 mg, or 100 mg) once a day co-formulated with the oral absorption enhancer sodium N-[8-(2-hydroxybenzoyl)amino] caprylate (500 mg); placebo; or open-label evolocumab (140 mg) every 2 weeks administered subcutaneously. Blinding was performed within each dose level. The primary endpoint was percentage change from baseline in LDL cholesterol measured by β quantification at week 12. All randomly assigned participants received at least one dose of treatment and were included in both safety and efficacy analyses. The trial was registered on ClinicalTrials.gov, NCT04992065, and is completed.

Findings

Between Aug 16, 2021, and Jan 28, 2022, we randomly assigned 267 patients to one of the three NNC0385-0434 dose cohorts (n=53 per cohort), matching placebo (n=54), or open-label evolocumab (n=54). The study population comprised 82 (31%) women and 185 (69%) men; mean age was 64·3 years (SD 9·0). Baseline mean LDL cholesterol concentration was 2·7 mmol/L (SD 0·8). Treatment with NNC0385-0434 resulted in reductions in LDL cholesterol from baseline to week 12, of 32·0 percentage points (95% CI 20·9 to 43·0) in the 15 mg cohort, 44·9 percentage points (33·8 to 56·0) in the 40 mg cohort, and 61·8 percentage points (50·7 to 72·9) in the 100 mg cohort, compared with the placebo group (p<0·0001 for each). Patients treated with evolocumab had similar LDL cholesterol reductions (59·6% [SE 4·1] decrease from baseline) to patients receiving NNC0385-0434 100 mg (56·2% [4·0]). The estimated treatment difference between NNC0385-0434 100 mg and evolocumab 140 mg was 3·4 percentage points [95% CI –7·8 to 14·7]. The most frequently reported adverse event was COVID-19, which affected 31 (12%) of 267 patients, with similar numbers across treatment groups. Investigative sites reported gastrointestinal disorders as the most frequent treatment-related adverse event (26 patients and 35 events total in the three NNC0385 cohorts and one patient and one event each in the placebo and evolocumab cohorts). No deaths or treatment-related serious adverse events occurred.

Interpretation

This study showed excellent 12-week LDL cholesterol lowering efficacy and good patient tolerance of an oral PCSK9 inhibitor, NNC0835-0434, similar to an injectable drug. However, the sponsor chose to discontinue further development of NNC0835-0434 due to portfolio considerations.

Funding

Novo Nordisk.

中文翻译：

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口服 NNC0385-0434 对高胆固醇血症的 PCSK9 抑制：一项随机、双盲、安慰剂对照和活性对照 2 期试验

背景

目前可用的针对前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型 (PCSK9) 的注射药物可降低血清 LDL 胆固醇并改善心血管结局。这项 2 期研究在接受口服降脂治疗的个体中评估了 NNC0385-0434（一种口服 PCSK9 抑制剂）。

方法

在这项随机、双盲、安慰剂对照和主动对照试验中，7 个国家（比利时、德国、希腊、日本、荷兰、波兰和美国）的 42 个研究中心招募了患有动脉粥样硬化性心血管疾病的个体（年龄≥40岁）或动脉粥样硬化性心血管疾病高危人群（年龄>50岁），LDL胆固醇浓度至少1·8mmol/L，正在接受最大耐受他汀类药物和稳定降脂治疗。该研究通过交互式网络响应系统随机分配参与者 (3:1) 每天一次接受与口服吸收促进剂钠 N-[8-共同配制的 NNC0385-0434（15 毫克、40 毫克或 100 毫克）(2-羟基苯甲酰基)氨基]辛酸酯(500毫克)；安慰剂; 或开放标签evolocumab （140 毫克），每 2 周皮下注射一次。在每个剂量水平内进行盲法。主要终点是第 12 周时通过 β 定量测量的 LDL 胆固醇相对于基线的百分比变化。所有随机分配的参与者都接受至少一剂治疗，并纳入安全性和有效性分析。该试验已在ClinicalTrials.gov上注册（NCT04992065）并已完成。

发现

2021年8月16日至2022年1月28日期间，我们将267名患者随机分配至三个NNC0385-0434剂量组之一（每组n = 53）、匹配安慰剂（n = 54）或开放标签evolocumab（n = 54）。 =54）。研究人群包括 82 名（31%）女性和 185 名（69%）男性；平均年龄为 64·3 岁 (SD 9·0)。基线平均 LDL 胆固醇浓度为 2·7 mmol/L (SD 0·8)。NNC0385-0434 治疗导致 LDL 胆固醇从基线到第 12 周降低 32·0 个百分点（95% CI 20·9 至 43·0），15 mg 队列中降低 44·9 个百分点（33·8）与安慰剂组相比，40 mg 组中的百分比为 56·0），100 mg 组中为 61·8 个百分点（50·7 至 72·9）（均 p<0·0001）。使用 evolocumab 治疗的患者与接受 NNC0385-0434 100 mg 治疗的患者具有相似的 LDL 胆固醇降低（较基线降低 59·6% [SE 4·1]）（56·2% [4·0]）。NNC0385-0434 100 mg 和 evolocumab 140 mg 之间的估计治疗差异为 3·4 个百分点 [95% CI –7·8 至 14·7]。最常报告的不良事件是 COVID-19，它影响了 267 名患者中的 31 名 (12%)，各个治疗组的人数相似。研究中心报告称，胃肠道疾病是最常见的治疗相关不良事件（三个 NNC0385 队列中总共有 26 名患者和 35 起事件，安慰剂和 evolocumab 队列中各有 1 名患者和 1 起事件）。没有发生死亡或与治疗相关的严重不良事件。

解释

这项研究表明，与注射药物类似，口服 PCSK9 抑制剂 NNC0835-0434 具有出色的 12 周 LDL 胆固醇降低功效和良好的患者耐受性。然而，出于投资组合的考虑，申办方选择停止 NNC0835-0434 的进一步开发。

资金

诺和诺德。