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 via 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 versus 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 是一种研究性吸入可溶性鸟苷酸环化酶刺激剂，假设可避免全身血管舒张的大多数副作用。

2 期 INSIGNIA-PAH （NCT04732221） 试验将接受稳定背景治疗的成人肺动脉高压 （PAH） 随机分配至 1：1：1：1 每日一次服用安慰剂、MK-5475 32 μg、100 μg 或 380 μg，通过干粉吸入给药 12 周。

目的是评估肺血管阻力 （PVR;主要）、6 分钟步行距离 （6MWD;次要）、其他选定的血液动力学参数以及 PAH 参与者的安全性和耐受性。

168 名参与者被随机分配到安慰剂组 （n=41）、MK-5475 32 μg （n=42）、100 μg （n=44） 和 380 μg （n=41）。中位年龄为 51 岁。大多数参与者是女性 （73.8%），被诊断患有特发性 PAH （63.7%），同时接受 5 型磷酸二酯酶抑制剂 （PDE5i;93.5%），并接受双重或三重联合治疗 （85.1%）。在第 12 周，安慰剂校正的 PVR 最小二乘均值变化为 -9.2%（95% CI -21.3%，2.9%;p=0.068），32 μg，-22.0%（95% CI -33.7%，-10.3%;p<0.001），380 μg MK-5475 为 -19.9%（95% CI -33.4%，-6.4%;p=0.002）。在 6MWD 中未观察到与安慰剂相比的治疗差异。治疗组之间的治疗相关不良事件和严重不良事件相似。3 名参与者死亡：2 名服用安慰剂，1 名服用 MK-5475 100 μg。一名参与者有症状性低血压，一名参与者有咯血 （均使用 MK-5475 100 μg）。

在接受稳定背景治疗（包括 PDE5i）的 PAH 参与者中，吸入 MK-5475 降低了 PVR，并且耐受性良好，没有证据表明存在全身副作用，例如低血压，表明肺选择性药效学效应。