molgramostim (Gramal)

The changing landscape of autoimmune pulmonary alveolar proteinosis.

Jouneau Stéphane S, McCarthy Cormac C

Pulmonary alveolar proteinosis (PAP) should be suspected when the classic imaging finding of a "crazy paving" pattern is seen on chest CT; however, this appearance can be subtle and PAP may present with a range of varying CT features. The diagnosis is confirmed by identifying eosinophilic extracellular material that stains positively with Periodic Acid-Schiff on bronchoalveolar lavage specimens. The autoimmune form of PAP (aPAP) is confirmed by detecting anti-GM-CSF antibodies in the patient's serum. We propose a novel classification with definite, probable and possible aPAP diagnosis based on various combination of chest CT, BAL and anti-GM-CSF antibodies. Historically, whole-lung lavage has been the first-line treatment and should be performed only in expert centres. Following positive results from recent randomised, placebo-controlled trials, inhaled GM-CSF supplementation with molgramostim or sargramostim is now equally positioned as first line therapy, WLL remaining the preferred option for patients with respiratory failure, particularly at the time of diagnosis. Rituximab and plasmapheresis may be prescribed as third- and fourth-line treatments, respectively, and lung transplantation may be considered for eligible patients with end-stage respiratory failure. A deeper understanding of aPAP pathogenesis has opened new therapeutic avenues, including the use of PPARγ agonists or statins; however, future research must define the optimal long-term treatment strategy and, crucially, establish clear evidence-based criteria for when therapy should be commenced.

Molgramostim improves exercise distance and duration in autoimmune pulmonary alveolar proteinosis: exploratory IMPALA-2 trial data.

McCarthy Cormac C, Bonella Francesco F, Inoue Yoshikazu Y, Trapnell Bruce C BC et al.

Inhaled granulocyte-macrophage colony-stimulating factor (molgramostim) as host-directed therapy for pneumonia-related acute respiratory distress syndrome: a multicentre, randomised, placebo-controlled phase 2a trial (GI-HOPE).

Herold Susanne S, Welte Tobias T, Zacharowski Kai K, Meybohm Patrick P et al.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances pulmonary host defence and promotes re-establishment of alveolar barrier function. We investigated the safety, feasibility and efficacy of nebulised recombinant human (rh)GM-CSF (molgramostim) in pneumonia-related acute respiratory distress syndrome (ARDS). In this multicentre, randomised, double-blind, parallel-group, placebo-controlled, investigator-initiated phase 2a trial, patients were randomised to receive nebulised low-dose (150 μg) or high-dose (450 μg) rhGM-CSF or placebo for 3 days. Bronchoalveolar lavage (BAL) was performed before the first dose and after dosing. The primary outcome parameter was the composite GI-HOPE score, representing expression changes of CD80, CD86, CD206 and human leukocyte antigen (HLA)-DR on alveolar macrophages after dosing compared to baseline. Secondary outcomes included oxygenation, Sequential Organ Failure Assessment (SOFA) scores and clinical end-points at day 28. 46 participants were randomised, 43 completed treatment (n=15 placebo, n=16 low dose and n=12 high dose), and BAL was performed on 38 participants before and after treatment. Although the composite biological GI-HOPE score did not reach significance (p>0.05), high-dose treatment caused upregulation of HLA-DR and CD206 on alveolar macrophages, indicating deposition in the alveolar compartment and beneficial macrophage activation (HLA-DR: p=0.0406 versus low dose, p=0.1841 versus placebo; CD206: p=0.009 versus low dose, p=0.0179 versus placebo). High-dose rhGM-CSF treatment revealed a favourable profile of oxygenation at the end of analysis compared to time-points before inhalation (p=0.095 and p=0.0175) or compared to the low-dose and placebo groups (p=0.0063 and p=0.0198; visit 13), and was associated with decreased SOFA scores in the high-dose group over time (p=0.0013 and p=0.00023 compared to low dose and placebo). Importantly, inhaled rhGM-CSF did not increase alveolar or systemic inflammation. Inhalation of 450 μg rhGM-CSF was safe, and promoted a favourable profile regarding alveolar macrophage activation, oxygenation and SOFA scores over time; however, it did not lead to differences in the GI-HOPE score.

Efficacy of recombinant human GM-CSF compared to placebo for autoimmune pulmonary alveolar proteinosis: a systematic review and meta-analysis.

Naeem Umaimah U, Zahid Hafiza Fatima HF, Imtiaz Sarah S, Khan Quratulain Q et al.

BACKGROUND: Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare interstitial lung disease characterized by surfactant accumulation within alveoli due to impaired clearance or GM-CSF signaling defect. Whole lung lavage (WLL) removes accumulated surfactant but is invasive and does not correct macrophages dysfunction. Recombinant GM-CSF (molgramostim or sargramostim) aims to restore macrophage activity¸ enhance gas exchange and reduce dependence on WLL. OBJECTIVE: This systematic review and meta-analysis evaluated the efficacy of recombinant human GM-CSF (molgramostim or sargramostim) compared with placebo in patients with aPAP. METHOD: Following PRISMA guidelines, PubMed, Cochrane CENTRAL, and Scopus were searched for randomized controlled trials in adults with aPAP receiving molgramostim or sargramostim versus placebo. Primary outcomes included changes in alveolar–arterial oxygen gradient (A-aDO₂) and diffusing capacity of the lung for carbon monoxide (DLCO). Secondary outcomes included St. George’s Respiratory Questionnaire (SGRQ) scores, radiologic ground-glass opacity (GGO) scores, vital capacity, six-minute walk distance, serum biomarkers (CEA and KL-6), and GM-CSF autoantibody levels. Data were analyzed using a random-effects model RevMan 5.4.1, and risk of bias with ROB 2.0. RESULT: Four RCTs involving 338 participants (190 interventions,148 control) were included. Recombinant GM-CSF significantly improved gas exchange, with decreased A-aDO₂ MD of -4.67 (95% CI: -8.49 to -1.42, p = 0.006) and increased DLCO (% predicted) with a mean difference of 6.13 (95% CI: 3.36 to 8.89). Significant improvements were also observed in SGRQ-T scores (MD = –6.60; p < 0.00001) and GGO scores (MD = –1.98; p = 0.0007). No significant differences were found for six-minute walk distance, vital capacity, or serum biomarkers. Most included trials showed low to moderate risk of bias with a few high risk. Egger’s test (p = 0.37) showed no publication bias and overall certainty of evidence ranged from moderate to high. CONCLUSION: Recombinant GM-CSF (molgramostim and sargramostim) is an effective, disease targeted therapy for aPAP. It improves pulmonary function gas exchange and radiological outcomes while reducing reliance on whole lung lavage. TRIAL REGISTRATION: PROSPERO reference number CRD420251165258.