Molgramostim: Inhaled GM-CSF for Autoimmune Pulmonary Alveolar Proteinosis

Table of Contents

1. The Disease in One Paragraph
2. How Inhaled GM-CSF Is Meant to Work
3. Whole Lung Lavage, the Older Standard
4. The Sargramostim Trials That Came First
5. IMPALA: Daily Against Every-Other-Week Dosing
6. IMPALA-2: Gas Transfer Over 48 Weeks
7. What the Pooled Analyses Found
8. Side Effects Reported
9. Where Guidelines and Reviews Place Inhaled GM-CSF
10. United States Regulatory Status
11. Other Lung Conditions Under Study
12. What Is Not Known
13. Key Research Papers
14. Connections
15. Featured Videos

The Disease in One Paragraph

In autoimmune pulmonary alveolar proteinosis, the air sacs of the lungs slowly fill with surfactant, the oily film that normally keeps them open. Surfactant is cleared by cleaning cells called alveolar macrophages, and those cells need GM-CSF to do the job. In this disease the immune system makes antibodies against GM-CSF, which block its signal, so the macrophages stop clearing surfactant, it builds up, and less oxygen gets from the air into the blood (Trapnell 2020; Trapnell 2025). A 2025 case series describes the autoimmune form as more than 90% of all cases of pulmonary alveolar proteinosis (Montaño 2025). A 2026 systematic review of 50 reports covering 2,855 patients found breathlessness, cough and sputum among the commonly reported symptoms, along with falling oxygen levels, reduced exercise capacity, reduced quality of life, more serious infections and frequent delays and misdiagnosis before the disease was recognised (McCarthy 2026, burden review). The causes, tests, scan patterns and the other forms of the disease are on the pulmonary alveolar proteinosis page.

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How Inhaled GM-CSF Is Meant to Work

The idea behind the treatment is to replace what the antibodies take away. If enough GM-CSF reaches the air sacs, some of it may get past the antibodies and reach the macrophages, which can then clear surfactant again. Reviews describe this as GM-CSF "augmentation" or "supplementation" therapy (McCarthy 2024; Jouneau 2025). Breathing the protein in puts it where the macrophages are, rather than spreading it through the whole body.

Two forms of laboratory-made GM-CSF have been tested this way. Molgramostim is one; the IMPALA trial report calls it "the recombinant GM-CSF molgramostim" and gave it as an inhaled solution (Trapnell 2020). Sargramostim is the other; the PAGE trial calls it "recombinant human GM-CSF (sargramostim)" (Tazawa 2019). A 2026 meta-analysis grouped both together as recombinant human GM-CSF (Naeem 2026).

What happens in the body after one breath

A phase 1 trial in 42 healthy adults gave single inhaled doses of 150, 300 or 600 micrograms, or six daily doses of 300 or 600 micrograms (Trapnell 2025, healthy-volunteer study). GM-CSF could be measured in the blood 30 minutes after inhalation and peaked at 2 hours, with an elimination half-life of between 1.7 and 5.9 hours across the groups. The amount reaching the blood was described as "picogram levels", and it did not rise in a straight line with the dose. White blood cell counts rose quickly and returned to normal by 8 hours after a single dose, or by 15 to 21 days after the six-day course. No dose-limiting safety concerns were seen and no antibodies against the drug formed. A breath test for airway inflammation (exhaled nitric oxide) stayed within the normal range, though it was numerically, not significantly, higher at the 600 microgram dose. As the paper discloses, one author is an employee of the drug's developer and another has served as its paid consultant.

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Whole Lung Lavage, the Older Standard

Before inhaled GM-CSF, the main treatment was whole lung lavage: under general anaesthesia, one lung at a time is filled with salt water and drained, washing the built-up surfactant out. A 2025 case series calls it the current standard of care and describes it as invasive, resource-intensive, carrying procedural risk, not addressing the underlying cause and often needing to be repeated (Montaño 2025). A 2024 trial report calls it a widely accepted palliative treatment that does not correct the underlying macrophage problem (Campo 2024). In the 2026 burden review, whole lung lavage was the therapy given most often and many patients needed repeat procedures (McCarthy 2026, burden review). How the procedure is done is described on the pulmonary alveolar proteinosis page.

A small Italian trial tested the two approaches together. Eighteen people with moderate-to-severe autoimmune pulmonary alveolar proteinosis all had a whole lung lavage first; nine were then given inhaled sargramostim and nine received no scheduled therapy, and all were followed for 30 months (Campo 2024). The time to the first "rescue" lavage was 30 months with sargramostim against 18 months without it. Seven of the nine untreated patients (78%) needed a rescue lavage, against one of the nine sargramostim patients (11%). Oxygen levels, gas transfer and blood markers of the disease also improved more in the sargramostim group, and no serious adverse events were reported. The trial was small, and two of its authors disclose consulting work on inhaled GM-CSF.

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The Sargramostim Trials That Came First

Molgramostim's trials followed earlier work with inhaled sargramostim, mainly in Japan.

The Japanese phase 2 study (2010)

Fifty patients at nine Japanese centres entered a 12-week observation period; those who improved on their own were excluded (Tazawa 2010). The rest received a higher-dose phase (250 micrograms on days 1 to 8 of each 14-day cycle, six cycles over 12 weeks) and then a lower-dose phase (125 micrograms on days 1 to 4 of each cycle, six cycles over 12 weeks). Of 35 patients who completed both phases, 24 improved, a response rate of 62% (24 of 39) by intention-to-treat analysis, and the gap between oxygen in the lungs and oxygen in the blood (the alveolar-arterial oxygen difference) narrowed by 12.3 mm Hg. Twenty-nine of the 35 stayed stable without further therapy for one year. No serious adverse events occurred. Blood levels of the anti-GM-CSF antibodies did not change. This study had no placebo group.

The PAGE trial (2019)

The PAGE trial was double-blind and placebo-controlled. It enrolled 64 people with autoimmune disease of mild-to-moderate severity, with an arterial oxygen pressure below 70 mm Hg (or below 75 mm Hg with symptoms); people with severe disease (below 50 mm Hg) were excluded to prevent possible worsening of the disease in patients assigned to placebo (Tazawa 2019). The trial gave inhaled sargramostim 125 micrograms twice daily for 7 days, every other week, for 24 weeks, or placebo. The alveolar-arterial oxygen gradient changed by -4.50 mm Hg with sargramostim against +0.17 mm Hg with placebo (P = 0.02), and lung density on computed tomography improved more with sargramostim. Serious adverse events occurred in 6 patients on sargramostim and 3 on placebo. The authors concluded that the drug had a "modest salutary effect" on arterial oxygen and that "no clinical benefits were noted".

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IMPALA: Daily Against Every-Other-Week Dosing

IMPALA was a double-blind, placebo-controlled trial of molgramostim with three groups (Trapnell 2020). The trial gave molgramostim 300 micrograms once daily by inhalation, either every day (continuous) or every other week (intermittent), or a matching placebo, for 24 weeks, followed by an open-label extension. Of 138 patients, 46 received continuous molgramostim, 45 intermittent molgramostim and 47 placebo.

• Main result: the alveolar-arterial oxygen gradient improved by 12.8 mm Hg with continuous molgramostim against 6.6 mm Hg with placebo, an estimated treatment difference of 6.2 mm Hg (P = 0.03).
• Quality of life: the St. George's Respiratory Questionnaire total score, a breathing-related quality-of-life score where lower is better, fell by 12.4 points with continuous molgramostim against 5.1 points with placebo, an estimated difference of 7.4 points (P = 0.01).
• Dosing schedule: for several outcomes, every-day dosing did better than every-other-week dosing.
• Safety: the share of patients with adverse events and with serious adverse events was similar in all three groups, except chest pain, which was more common with continuous dosing.

A plain-language summary of IMPALA written by its lead author adds that the amount of surfactant seen on scans, and the number of whole lung lavages patients needed, were lower with daily molgramostim than with placebo; that summary gives no figures for these (Trapnell 2024). The trial was funded by the drug's developer.

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IMPALA-2: Gas Transfer Over 48 Weeks

IMPALA-2 was the larger phase 3 trial (Trapnell 2025). It gave 164 patients either molgramostim 300 micrograms or placebo once daily for 48 weeks; 81 received molgramostim and 83 placebo. This time the main measure was not the oxygen gradient but the diffusing capacity of the lungs for carbon monoxide, a breathing test of how well gas passes from the air sacs into the blood, expressed as a percentage of the value predicted for a healthy person of the same build. Here it is called gas transfer.

• Gas transfer at 24 weeks (main result): rose 9.8 percentage points with molgramostim against 3.8 with placebo, an estimated difference of 6.0 percentage points (P < 0.001).
• Gas transfer at 48 weeks: rose 11.6 percentage points with molgramostim against 4.7 with placebo (P < 0.001).
• Quality-of-life total score at 24 weeks: fell 11.5 points with molgramostim against 4.9 with placebo (P = 0.007).
• Activity score: the activity part of the same questionnaire showed no significant difference between the groups at 24 weeks.
• Safety: the share of patients with at least one adverse event, and with at least one serious adverse event, was similar in the two groups.

The trial tested its secondary results in a fixed order. Because the activity score did not differ, the authors drew no statistical conclusion about the results that came after it in that order, which include exercise capacity at 24 and 48 weeks (Trapnell 2025). A separate 2026 report is titled as showing that molgramostim improved exercise distance and duration in "exploratory" IMPALA-2 data (McCarthy 2026, exploratory report); its abstract was not available when this page was written, so no figures from it appear here. The trial was funded by the drug's developer.

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What the Pooled Analyses Found

Three meta-analyses have combined the randomised trials of inhaled GM-CSF, mixing molgramostim and sargramostim. They counted the trials slightly differently.

• 2023, three studies pooled (Munsif 2023): the quality-of-life score improved by 8.09 points, gas transfer by 5.09 percentage points and the alveolar-arterial oxygen gradient by 4.36 mm Hg. Six-minute walking distance rose by 21.72 metres, but this was not statistically significant (p = 0.08). No serious trial-related adverse events were reported.
• 2026, four trials, 338 participants (Naeem 2026): the oxygen gradient fell by 4.67 mm Hg, gas transfer rose by 6.13 percentage points, the quality-of-life score fell by 6.60 points and the hazy shadowing on scans (ground-glass opacity score) improved. No significant differences were found for six-minute walking distance, vital capacity or blood markers.
• 2026, four phase 3 trials, 402 patients (Dang 2026): gas transfer rose by 5.09 percentage points and the oxygen gradient fell by 4.25 mm Hg, with breathlessness scores improving. No significant improvement was seen in lung volume or exercise capacity. Continuous and intermittent schedules showed comparable results and side effects.

The three agree on the direction of the gas-exchange results. None of them found a significant improvement in walking distance or exercise capacity.

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Side Effects Reported

The published abstracts describe side effects in general terms rather than as long lists.

• Chest pain: the one adverse event IMPALA found more often with daily molgramostim than with placebo (Trapnell 2020).
• Overall adverse events: similar between molgramostim and placebo in IMPALA and in IMPALA-2, both for any adverse event and for serious ones (Trapnell 2020; Trapnell 2025).
• White blood cells: in healthy volunteers, inhaled molgramostim caused a quick rise in white blood cell counts that returned to normal, mostly staying within normal ranges (Trapnell 2025, healthy-volunteer study).
• Antibodies against the drug: none formed in the healthy-volunteer study (Trapnell 2025, healthy-volunteer study).
• Sargramostim: serious adverse events in 6 patients on inhaled sargramostim against 3 on placebo in PAGE (Tazawa 2019); none in the Japanese phase 2 study (Tazawa 2010) or the Italian lavage-plus-sargramostim trial (Campo 2024).

Of the two inhaled GM-CSF drugs, only sargramostim has a US label on DailyMed, and that label covers injections given for blood and bone-marrow problems; it does not describe inhaled use.

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Where Guidelines and Reviews Place Inhaled GM-CSF

In 2024 the European Respiratory Society published the first guidelines for diagnosing and managing pulmonary alveolar proteinosis (McCarthy 2024). Its task force made recommendations on whole lung lavage, GM-CSF augmentation therapy, rituximab, plasmapheresis and lung transplantation. Its summary adds that several therapies are available, "but supporting evidence is still limited".

Later reviews led by an IMPALA investigator who also co-wrote the guideline describe how the field has shifted. A 2025 review states that inhaled GM-CSF, either molgramostim or sargramostim, "is now considered a first-line treatment in the international guidelines", while whole lung lavage "remains the preferred treatment for patients experiencing respiratory failure, especially at the time of diagnosis"; it lists rituximab and plasmapheresis as third- and fourth-line options (Jouneau 2025). A 2026 review states that inhaled GM-CSF is "now equally positioned as first line therapy" alongside lavage (Jouneau 2026). Both reviews disclose their authors' roles in the IMPALA trials and the guideline.

A 2026 long-term study from one Japanese centre adds a different angle (Yamaguchi 2026). Among 64 patients followed for a median of 7.8 years, 45.3% improved, 40.6% stayed stable and 14.1% got worse. In that analysis, a worse starting score, better starting lung volume and no scarring pattern on scans were linked to improvement, while whole lung lavage and GM-CSF inhalation were not. The anti-GM-CSF antibodies fell over time in 51 of 52 patients tested, with an estimated half-life of 3.5 years, and GM-CSF inhalation was linked to lower final antibody levels. In the shorter 2010 Japanese trial, by contrast, blood antibody levels were unchanged during treatment (Tazawa 2010). The 2026 study was retrospective and could not prove cause and effect.

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United States Regulatory Status

On 13 November 2026, a search of DailyMed, the US National Library of Medicine's database of drug labels, returned no label for molgramostim. Papers published in 2025 describe molgramostim inhalation solution as "investigational" (Montaño 2025; Trapnell 2025, healthy-volunteer study). No source read for this page reported a US approval decision, so none is stated here.

Sargramostim does have a US label on DailyMed, as an injection. Its listed uses are: shortening the time to neutrophil recovery after induction chemotherapy for acute myeloid leukemia in adults 55 and older; collecting blood stem cells for transplant; speeding the recovery of blood-forming cells after bone-marrow or stem-cell transplant; treating delayed recovery or graft failure after transplant; and improving survival after exposure to high doses of radiation. Pulmonary alveolar proteinosis is not among the listed uses, and the label does not describe inhaled use.

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Other Lung Conditions Under Study

Because GM-CSF strengthens the lung's macrophages, inhaled molgramostim has also been tried in lung infections.

• Nontuberculous mycobacterial infection: the OPTIMA pilot trial gave 32 adults with hard-to-treat lung infection molgramostim 300 micrograms a day for 48 weeks, with or without their usual antibiotic regimen (Thomson 2024). Eight (25%) reached culture conversion, meaning three negative monthly sputum cultures in a row during treatment: seven of 24 (29.2%) with Mycobacterium avium complex and one of eight (12.5%) with Mycobacterium abscessus; in four this lasted after treatment ended. Other clinical measures were unchanged. Serious adverse events were mainly flare-ups of lung disease or worsening infection, and three deaths were reported by the authors as not related to treatment. There was no comparison group.
• Pneumonia-related acute respiratory distress syndrome: the GI-HOPE phase 2a trial randomised 46 patients to inhaled molgramostim 150 or 450 micrograms or placebo for 3 days (Herold 2026). Its main combined macrophage score did not differ between the groups. The higher dose raised two macrophage activation markers, one of them significantly against placebo, and was linked to better oxygenation and lower organ-failure scores over time, and the treatment did not increase inflammation in the lungs or the body.

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What Is Not Known

• Whether it helps people move more. IMPALA-2 drew no statistical conclusion on exercise capacity, and none of the three meta-analyses found a significant gain in walking distance or exercise capacity (Trapnell 2025; Munsif 2023; Naeem 2026; Dang 2026). An exploratory IMPALA-2 report is titled as showing better exercise distance and duration (McCarthy 2026, exploratory report).
• How it compares with whole lung lavage head to head. The 2023 meta-analysis called for research comparing the two "in key clinical outcomes", including patient choice (Munsif 2023).
• How it compares with sargramostim. None of the papers read for this page compared molgramostim directly with sargramostim; the meta-analyses pooled them.
• Long-term results. The placebo-controlled molgramostim results described here run to 48 weeks (Trapnell 2025). Beyond that, the published experience includes a case series of five patients given molgramostim, described by its authors as showing beneficial long-term effects; its authors report support from the drug's developer (Montaño 2025).
• When to start. A 2026 review states that future research must establish "clear evidence-based criteria" for when to begin therapy (Jouneau 2026).
• Other forms of the disease. The molgramostim trials described here enrolled people with the autoimmune form only (Trapnell 2020; Trapnell 2025).

Decisions about any medicine for this disease belong with the lung specialists who treat it.

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Key Research Papers

1. Trapnell BC, Inoue Y, Bonella F, Morgan C, Jouneau S, Bendstrup E, et al. Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis. N Engl J Med. 2020;383(17):1635-1644. PubMed PMID: 32897035
2. Trapnell BC, Inoue Y, Bonella F, Wang T, McCarthy C, Arai T, et al. Phase 3 Trial of Inhaled Molgramostim in Autoimmune Pulmonary Alveolar Proteinosis. N Engl J Med. 2025;393(8):764-773. PubMed PMID: 40834301
3. McCarthy C, Bonella F, Inoue Y, Trapnell BC, Wang T, Ataya A, et al. Molgramostim improves exercise distance and duration in autoimmune pulmonary alveolar proteinosis: exploratory IMPALA-2 trial data. Ann Am Thorac Soc. 2026:aaoag301. PubMed PMID: 42770839
4. Trapnell BC. Inhaled molgramostim therapy for the treatment of autoimmune pulmonary alveolar proteinosis (aPAP): a plain language summary of the IMPALA trial. Hosp Pract (1995). 2024;52(3):47-63. PubMed PMID: 39165153
5. Trapnell BC, Carey BC, Robinson BR. Pharmacokinetics and pharmacodynamics of inhaled molgramostim in healthy people. BMJ Open Respir Res. 2025;12(1):e002832. PubMed PMID: 40973220
6. Montaño C, Bendstrup E, Rønnov-Jessen I, Salgado S, Sterniste G, Valipour A, et al. Long-term outcomes in five patients with autoimmune pulmonary alveolar proteinosis treated with molgramostim inhalation solution. ERJ Open Res. 2025;11(1):00567-2024. PubMed PMID: 39872386
7. Tazawa R, Ueda T, Abe M, Tatsumi K, Eda R, Kondoh S, et al. Inhaled GM-CSF for Pulmonary Alveolar Proteinosis. N Engl J Med. 2019;381(10):923-932. PubMed PMID: 31483963
8. Tazawa R, Trapnell BC, Inoue Y, Arai T, Takada T, Nasuhara Y, et al. Inhaled granulocyte/macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis. Am J Respir Crit Care Med. 2010;181(12):1345-1354. PubMed PMID: 20167854
9. Campo I, Carey BC, Paracchini E, Kadija Z, De Silvestri A, Rodi G, et al. Inhaled recombinant GM-CSF reduces the need for whole lung lavage and improves gas exchange in autoimmune pulmonary alveolar proteinosis patients. Eur Respir J. 2024;63(1):2301233. PubMed PMID: 37973175
10. Munsif M, Sweeney D, Leong TL, Stirling RG. Nebulised granulocyte-macrophage colony-stimulating factor (GM-CSF) in autoimmune pulmonary alveolar proteinosis: a systematic review and meta-analysis. Eur Respir Rev. 2023;32(170):230080. PubMed PMID: 37993127
11. Naeem U, Zahid HF, Imtiaz S, Khan Q, Iftikhar A, Azmat A, et al. Efficacy of recombinant human GM-CSF compared to placebo for autoimmune pulmonary alveolar proteinosis: a systematic review and meta-analysis. BMC Pulm Med. 2026;26(1):148. PubMed PMID: 41742124
12. Dang M, Raj A, Motawea AG, Paramkusam SMC, Fatukasi SP, Paramkusam AV, et al. Efficacy and Safety of Inhaled GM-CSF in Autoimmune Pulmonary Alveolar Proteinosis: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Lung. 2026;204(1):23. PubMed PMID: 42045620
13. McCarthy C, Bonella F, O'Callaghan M, Dupin C, Alfaro T, Fally M, et al. European Respiratory Society guidelines for the diagnosis and management of pulmonary alveolar proteinosis. Eur Respir J. 2024;64(5):2400725. PubMed PMID: 39147411
14. Jouneau S, Chauvin P, Lederlin M, Painvin B, Kerjouan M. Pharmacotherapy for Autoimmune Pulmonary Alveolar Proteinosis. Drugs. 2025;85(10):1193-1206. PubMed PMID: 40866780
15. Jouneau S, McCarthy C. The changing landscape of autoimmune pulmonary alveolar proteinosis. Respir Med Res. 2026;90:101335. PubMed PMID: 43014030
16. McCarthy C, Bonella F, Wang T, Inoue Y, Robinson B, Trapnell BC. The burden of autoimmune pulmonary alveolar proteinosis: a systematic review. Eur Respir Rev. 2026;35(180):250237. PubMed PMID: 41951241
17. Yamaguchi E, Tanaka H, Fujishiro E, Fukami M, Katano T, Ito S. A long-term observational study on autoimmune pulmonary alveolar proteinosis revealed a sustained and generalized decrease in serum autoantibody levels. Orphanet J Rare Dis. 2026;21(1):190. PubMed PMID: 41808122
18. Thomson RM, Loebinger MR, Burke AJ, Morgan LC, Waterer GW, Ganslandt C. OPTIMA: An Open-Label, Noncomparative Pilot Trial of Inhaled Molgramostim in Pulmonary Nontuberculous Mycobacterial Infection. Ann Am Thorac Soc. 2024;21(4):568-576. PubMed PMID: 37948736
19. Herold S, Welte T, Zacharowski K, Meybohm P, Bauer M, Wilhelm J, 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). ERJ Open Res. 2026;12(5):01795-2025. PubMed PMID: 42769414

PubMed Topic Searches

1. PubMed: molgramostim in pulmonary alveolar proteinosis
2. PubMed: inhaled sargramostim in pulmonary alveolar proteinosis
3. PubMed: randomised trials of inhaled GM-CSF
4. PubMed: whole lung lavage in autoimmune pulmonary alveolar proteinosis

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Connections

• Drugs — the parent hub for every drug page
• Pulmonary Alveolar Proteinosis — the disease, its forms, tests and whole lung lavage
• Pulmonology — the lung disease section
• Surfactant: Why Your Lungs Don’t Collapse — the film that builds up in this disease
• Silicosis — acute silica exposure can mimic pulmonary alveolar proteinosis
• Leukopenia — where colony-stimulating factors are used for low white cell counts
• Acute Respiratory Distress Syndrome — another condition where inhaled molgramostim was tested
• Nocardiosis — one of the infections linked to pulmonary alveolar proteinosis

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