近日，美国辛辛那提儿童医院医疗中心Bruce C. Trapnell团队研究了Molgramostim治疗自身免疫性肺泡蛋白沉积症的疗效与安全性。2025年8月21日出版的《新英格兰医学杂志》发表了这项成果。

自身免疫性肺泡蛋白沉积症（aPAP）是一种罕见的疾病，其特征是进行性表面活性剂积累和低氧血症，由抗粒细胞-巨噬细胞集落刺激因子（GM-CSF）的自身抗体引起，肺泡巨噬细胞需要清除表面活性剂。Molgramostim是一种吸入式重组人GM-CSF制剂，但其在aPAP患者中的疗效和安全性尚未得到充分研究。

在这项3期、双盲、安慰剂对照试验中，研究组随机分配aPAP患者接受300 μg剂量的Molgramostim或安慰剂，每天1次，持续48周。主要终点是从基线到第24周肺部一氧化碳弥散能力（DLCO）的变化，根据血红蛋白浓度进行调整，并以预测值的百分比表示。经多重性调整的次要终点是48周时DLCO与基线的变化，以及24周和48周时圣乔治呼吸问卷总分（SGRQ-T）和活动量（SGRQ-A）评分（评分范围从0到100，分数越低表明生活质量越好）和运动能力的变化。

共有164名患者接受了随机分组：81名患者接受Molgramostim治疗，83名患者接受安慰剂治疗。从基线到第24周，Molgramostim组DLCO的最小二乘平均变化为9.8个百分点（95%置信区间，7.3至12.3），安慰剂组为3.8个百分点（95% CI， 1.4至6.3）（估计治疗差异，6.0个百分点；95% CI， 2.5至9.4;P<0.001）。从基线到第48周，molgramostim组DLCO的最小二乘平均变化为11.6个百分点（95% CI， 8.7至14.5），安慰剂组为4.7个百分点（95% CI， 1.8至7.6）（P<0.001），第24周SGRQ-T评分的最小二乘平均变化分别为11.5个百分点（95% CI， 15.0至8.0）和4.9个百分点（95% CI， 8.3至1.5）（P=0.007）。在24周时，SGRQ-A评分的变化在组间无显著差异，因此对随后的次要终点没有统计学推断。在两组中，至少发生一次不良事件的患者百分比和至少发生一次严重不良事件的患者百分比相似。

研究结果表明，在aPAP患者中，每日一次吸入Molgramostim导致肺气体转移比安慰剂增加。

附：英文原文

Title: Phase 3 Trial of Inhaled Molgramostim in Autoimmune Pulmonary Alveolar Proteinosis

Author: Bruce C. Trapnell, Yoshikazu Inoue, Francesco Bonella, Tisha Wang, Cormac McCarthy, Toru Arai, Keiichi Akasaka, Francesca Mariani, Nesrin Mogulkoc, Jin Woo Song, Tomohisa Baba, Stephane Jouneau, Tadahisa Numakura, Nesrin cal, Florin Mihaltan, Ali Ataya, Elisabeth Bendstrup, Ilaria Campo, Brenna Carey, Ross Arena, Brian Robinson, Rosanna Fleming, Yasmine Wasfi, Raymond Pratt

Issue&Volume: 2025-08-21

Abstract:

Background

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia caused by autoantibodies against granulocyte–macrophage colony-stimulating factor (GM-CSF), which alveolar macrophages require to clear surfactant. Molgramostim is a formulation of inhaled recombinant human GM-CSF, but its efficacy and safety in patients with aPAP have not been studied sufficiently.

Methods

In this phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with aPAP to receive molgramostim at a dose of 300 μg or placebo once daily for 48 weeks. The primary end point was the change from baseline to week 24 in the diffusing capacity of the lungs for carbon monoxide (DLCO), which was adjusted for hemoglobin concentration and expressed as a percentage of the predicted value. Secondary end points adjusted for multiplicity were the change from baseline in DLCO at 48 weeks and the change from baseline in the St. George’s Respiratory Questionnaire total (SGRQ-T) and activity (SGRQ-A) scores (scores range from 0 to 100, with lower scores indicating better quality of life) and in exercise capacity at 24 and 48 weeks.

Results

A total of 164 patients underwent randomization: 81 were assigned to receive molgramostim and 83 to receive placebo. The least-squares mean change in DLCO from baseline to week 24 was 9.8 percentage points (95% confidence interval [CI], 7.3 to 12.3) with molgramostim and 3.8 percentage points (95% CI, 1.4 to 6.3) with placebo (estimated treatment difference, 6.0 percentage points; 95% CI, 2.5 to 9.4; P<0.001). The least-squares mean change in DLCO from baseline to week 48 was 11.6 percentage points (95% CI, 8.7 to 14.5) with molgramostim and 4.7 percentage points (95% CI, 1.8 to 7.6) with placebo (P<0.001), and the least-squares mean change in the SGRQ-T score at week 24 was 11.5 points (95% CI, 15.0 to 8.0) and 4.9 points (95% CI, 8.3 to 1.5), respectively (P=0.007). No significant between-group difference in the change in SGRQ-A score was observed at 24 weeks, so no statistical inference was drawn with respect to subsequent secondary end points. The percentage of patients with at least one adverse event and the percentage with at least one serious adverse event were similar in the two groups.

Conclusions

Once-daily inhaled molgramostim led to a greater increase in pulmonary gas transfer than placebo in patients with aPAP.

DOI: NJ202508213930808

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2410542