MRL, Merck & Co., Inc., Rahway, NJ, USA.
Translational Medicine, MSD Belgium, Brussels, Belgium.
Int J Chron Obstruct Pulmon Dis. 2024 May 23;19:1105-1121. doi: 10.2147/COPD.S454905. eCollection 2024.
This phase 1 study (NCT04370873) evaluated safety and pharmacokinetics/pharmacodynamics (PK/PD) of MK-5475 in participants with pulmonary hypertension associated with COPD (PH-COPD).
Eligible participants were 40-80 years old with COPD (FEV/FVC <0.7; FEV >30% predicted) and PH (mean pulmonary arterial pressure ≥25 mmHg). Participants were randomized 2:1 to MK-5475 or placebo via dry-powder inhaler once daily for 7 days in Part 1 (360 µg) or 28 days in Part 2 (380 µg). Safety was assessed by adverse events (AEs) and arterial blood oxygenation. Part-2 participants had pulmonary vascular resistance (PVR; primary PD endpoint) and pulmonary blood volume (PBV; secondary PD endpoint) measured at baseline and Day 28. A non-informative prior was used to calculate posterior probability (PP) that the between-group difference (MK-5475 - placebo) in mean percent reduction from baseline in PVR was less than -15%.
Nine participants were randomized in Part 1, and 14 participants in Part 2. Median age of participants (86.4% male) was 68.5 years (41-77 years); 95.5% had moderate-to-severe COPD. Incidences of AEs were comparable between MK-5475 and placebo: overall (5/14 [36%] versus 5/8 [63%]), drug-related (1/14 [7%] versus 2/8 [25%]), and serious (1/14 [7%] versus 1/8 [13%]). MK-5475 caused no meaningful changes in arterial blood oxygenation or PBV. MK-5475 versus placebo led to numerical improvements from baseline in PVR (-21.2% [95% CI: -35.4, -7.0] versus -5.4% [95% CI: -83.7, 72.9]), with between-group difference in PVR less than -15% and calculated PP of 51%.
The favorable safety profile and numerical reductions in PVR observed support further clinical development of inhaled MK-5475 for PH-COPD treatment.
这项 1 期研究（NCT04370873）评估了 MK-5475 在伴有 COPD 的肺动脉高压（PH-COPD）患者中的安全性和药代动力学/药效学（PK/PD）。
符合条件的参与者年龄在 40-80 岁，患有 COPD（FEV/FVC<0.7；FEV>30%预测值）和 PH（平均肺动脉压≥25mmHg）。参与者按 2:1 的比例随机分配至 MK-5475 或安慰剂组，通过干粉吸入器每日 1 次给药，第 1 部分（360μg）给药 7 天，第 2 部分（380μg）给药 28 天。通过不良事件（AE）和动脉血氧饱和度评估安全性。第 2 部分参与者在基线和第 28 天测量肺血管阻力（PVR；主要 PD 终点）和肺血容量（PBV；次要 PD 终点）。使用无信息先验计算从基线平均 PVR 降低百分比的组间差异（MK-5475-安慰剂）小于-15%的后验概率（PP）。
第 1 部分有 9 名参与者随机分组，第 2 部分有 14 名参与者随机分组。参与者的中位年龄（95.5%为男性）为 68.5 岁（41-77 岁）；95.5%患有中重度 COPD。MK-5475 与安慰剂的 AE 发生率相似：总体（5/14[36%]比 5/8[63%]）、药物相关（1/14[7%]比 2/8[25%]）和严重（1/14[7%]比 1/8[13%]）。MK-5475 未引起动脉血氧饱和度或 PBV 的明显变化。MK-5475 与安慰剂相比，基线 PVR 有数值改善（-21.2%[95%CI：-35.4，-7.0]比-5.4%[95%CI：-83.7，72.9]），组间 PVR 差异小于-15%，计算出的 PP 为 51%。
观察到的良好安全性和 PVR 的数值降低支持进一步开发吸入 MK-5475 治疗 PH-COPD。
