Université Paris-Saclay, Faculté de Médecine, Inserm UMR_S 999, Service de Pneumologie et Soins Intensifs Respiratoires, Hôpital Bicêtre (Assistance Publique - Hôpitaux de Paris), Le Kremlin-Bicêtre, France
Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Eur Respir J. 2024 Nov 14;64(5). doi: 10.1183/13993003.01110-2024. Print 2024 Nov.
MK-5475 is an investigational inhaled soluble guanylate cyclase stimulator hypothesised to avoid most side-effects of systemic vasodilation.
The phase 2 INSIGNIA-PAH (NCT04732221) trial randomised adults with pulmonary arterial hypertension (PAH) on stable background therapy 1:1:1:1 to once-daily dosing with placebo, MK-5475 32 µg, 100 µg or 380 µg dry powder inhalation for 12 weeks.
The objectives were to evaluate pulmonary vascular resistance (PVR; primary), 6-min walk distance (6MWD; secondary), additional selected haemodynamic parameters, and safety and tolerability in participants with PAH.
168 participants were randomised to placebo (n=41), MK-5475 32 µg (n=42), 100 µg (n=44), and 380 µg (n=41). Median age was 51 years. Most participants were female (73.8%), diagnosed with idiopathic PAH (63.7%), receiving concomitant phosphodiesterase type 5 inhibitors (PDE5i; 93.5%), and treated with double or triple combination therapy (85.1%). At week 12, the placebo-corrected changes in PVR by least-squares means were -9.2% (95% CI -21.3%, 2.9%; p=0.068) with 32 µg, -22.0% (95% CI -33.7%, -10.3%; p<0.001) with 100 µg, and -19.9% (95% CI -33.4%, -6.4%; p=0.002) with 380 µg MK-5475. No treatment differences placebo were observed in 6MWD. Treatment-related adverse events and serious adverse events were similar across treatment groups. Three participants died: two on placebo and one on MK-5475 100 µg. One participant had symptomatic hypotension and one had haemoptysis (both on MK-5475 100 µg).
In participants with PAH on stable background therapy, including PDE5i, inhaled MK-5475 reduced PVR and was well tolerated, without evidence of systemic side-effects such as hypotension, suggesting a pulmonary selective pharmacodynamic effect.
MK-5475 是一种研究中的吸入可溶性鸟苷酸环化酶刺激剂，据推测可避免全身血管扩张的大多数副作用。
这项 2 期 INSIGNIA-PAH 试验（NCT04732221）将肺动脉高压（PAH）患者按 1:1:1:1 的比例随机分为安慰剂、MK-5475 32μg、100μg 或 380μg 干粉吸入，每天一次，共 12 周。
本研究的目的是评估肺动脉阻力（PVR；主要终点）、6 分钟步行距离（6MWD；次要终点）、其他选定的血流动力学参数以及接受治疗的 PAH 患者的安全性和耐受性。
168 名患者被随机分为安慰剂（n=41）、MK-5475 32μg（n=42）、100μg（n=44）和 380μg（n=41）组。中位年龄为 51 岁。大多数患者为女性（73.8%），诊断为特发性 PAH（63.7%），同时接受磷酸二酯酶 5 抑制剂（PDE5i；93.5%）治疗，并接受双重或三重联合治疗（85.1%）。在第 12 周时，最小二乘法估计的安慰剂校正后 PVR 变化分别为 -9.2%（95%CI-21.3%，2.9%；p=0.068）、-22.0%（95%CI-33.7%，-10.3%；p<0.001）和 -19.9%（95%CI-33.4%，-6.4%；p=0.002）。与安慰剂相比，MK-5475 100μg 治疗组的 6MWD 无差异。各组治疗相关不良事件和严重不良事件相似。有 3 名患者死亡：2 名在安慰剂组，1 名在 MK-5475 100μg 组。1 名患者出现症状性低血压，1 名患者出现咯血（均在 MK-5475 100μg 组）。
在接受稳定背景治疗的 PAH 患者中，包括 PDE5i 在内，吸入 MK-5475 可降低 PVR，且耐受性良好，无低血压等全身副作用的证据，提示存在肺选择性药效学作用。
