Clinical Trial of Inhaled Molgramostim Nebulizer Solution in Autoimmune Pulmonary Alveolar Proteinosis (aPAP)

This is an interventional, randomized, double-blind, 2-arm, parallel groups, placebo-controlled, multi-center, phase 3 trial in adult subjects who are diagnosed with aPAP.

An aPAP diagnosis should be confirmed by a Granulocyte-macrophage colony stimulating factor (GM-CSF) auto-antibody test result, and history of PAP based on either high resolution computed tomography, lung biopsy, or bronchoalveolar lavage cytology, should be available.

The trial consists of a 6-week screening period, a 48-week randomized, double-blind treatment period, a 96-week open-label treatment period, and a conditional 4-week safety follow-up period. The maximum treatment duration will be 145 weeks and the maximum trial duration will be 156 weeks. During the trial, whole lung lavage will be allowed as rescue treatment in case of worsening of aPAP.

• Molgramostim (Drug), also known as Recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF): Molgramostim 300 µg nebulizer solution
• Placebo (Drug), also known as Placebo nebulizer: Matching placebo nebulizer solution
• Molgramostim Open-label (Drug), also known as Recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF): Molgramostim 300 µg nebulizer solution

Primary outcomes

• Change From Baseline in Percent (%) Predicted Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) Adjusted for Hemoglobin Concentration to Week 24 [From Baseline to Week 24]: As a measure of pulmonary gas transfer, a standardized lung function test, DLCO, was conducted. The single-breath DLCO test was performed in accordance with American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines for DLCO testing. Results reported as % predicted DLCO adjusted for hemoglobin concentration (%predicted DLCOadj).

Secondary outcomes

• Change From Baseline in Percent (%) Predicted DLCO Adjusted for Hemoglobin Concentration (%DLCOadj) to Week 48 [From Baseline to Week 48]: As a measure of pulmonary gas transfer, a standardized lung function test, DLCO, was conducted. The single-breath DLCO test was performed in accordance with American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines for DLCO testing. Results reported as % predicted DLCO adjusted for hemoglobin concentration (%predicted DLCOadj). Higher values indicate better respiratory gas exchange.
• Change From Baseline in St. Georges Respiratory Questionnaire (SGRQ) Total Score to Week 24 [From Baseline to Week 24]: The Saint Georges Respiratory Questionnaire (SGRQ) is designed to measure respiratory health impairment. The scale includes questions related to three components: Activity (activities that cause or are limited by breathlessness), Impact (social functioning and psychological disturbances resulting from airway disease), and Symptoms (respiratory symptoms, their frequency and severity). The questionnaire has a recall period of 4 weeks for Symptoms, whereas Activity and Impact components address the subject's current state. SGRQ scored on a 0-100 scale with lower scores indicating better respiratory health.
• Change From Baseline in SGRQ Activity Component Score to Week 24 [From Baseline to Week 24]: The Saint Georges Respiratory Questionnaire (SGRQ) Activity scale is a subscale of the SGRQ and is designed to measure the effect of respiratory health impairment on daily activity affected by breathlessness. The questionnaire for the Activity components addresses the subject's current state. SGRQ Activity is scored on a 0-100 scale with lower scores indicating better respiratory health activity
• Change From Baseline in Exercise Capacity (EC), Expressed as Peak Metabolic Equivalents (METs) to Week 24 [From Baseline to Week 24]: As a functional measure of exertional limitations related to dyspnea, EC was assessed by an exercise treadmill test. EC was expressed in peak METs (1 MET=3.5 mL O2/kg/min). The highest treadmill speed and grade achieved was used to calculate peak METs. Higher values indicate better functional capacity.
• Change From Baseline in SGRQ Total Score to Week 48 [From Baseline to Week 48]: The Saint Georges Respiratory Questionnaire (SGRQ) is designed to measure respiratory health impairment. The scale includes questions related to three components: Activity (activities that cause or are limited by breathlessness), Impact (social functioning and psychological disturbances resulting from airway disease), and Symptoms (respiratory symptoms, their frequency and severity). The questionnaire has a recall period of 4 weeks for Symptoms, whereas Activity and Impact components address the subject's current state. SGRQ scored on a 0-100 scale with lower scores indicating better respiratory health.
• Change From Baseline in SGRQ Activity From Baseline to Week 48 [From Baseline to Week 48]: The Saint Georges Respiratory Questionnaire (SGRQ) Activity scale is a subscale of the SGRQ and is designed to measure the effect of respiratory health impairment on daily activity affected by breathlessness. The questionnaire for the Activity components addresses the subject's current state. SGRQ Activity is scored on a 0-100 scale with lower scores indicating better respiratory health activity
• Change From Baseline in EC, Expressed as Peak METs to Week 48 [From Baseline to Week 48]: As a functional measure of exertional limitations related to dyspnea, EC was assessed by an exercise treadmill test. EC was expressed in peak METs (1 MET=3.5 mL O2/kg/min). The highest treadmill speed and grade achieved was used to calculate peak METs. Higher values indicate better functional capacity.
• Change From Baseline in Alveolar-arterial Oxygen Difference (A-aDO2) to Week 24 (All Subjects) [From Baseline to Week 24]: A-aDO2 was used as an additional measure of gas exchange.
• Number of Subjects With Serious and Non-serious Adverse Events [From Baseline until End of Double-blind treatment (Week 48)]: Assessment of the safety of molgramostim compared to placebo
• Number of Subjects With Positive Treatment-boosted Anti Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) Antibody Titers During 24 Weeks' Treatment and During 48 Weeks' Treatment [From Baseline until End of Double-blind treatment Week-48]: Assess the effect of molgramostim or placebo on antiGM-CSF antibody titers that increased by a dilution factor of 2.(4X increase in titer compared to Baseline).
• Changes in Forced Vital Capacity (FVC) %Predicted Normal [From Baseline to Weeks 24 and 48]: Forced vital capacity is the volume of air that can be expired after a deep breath. Higher volumes indicate better respiratory function. FVC is scored as % of predicted normal expired vital capacity.
• Changes in Forced Expiratory Volume in One Second (FEV1) % Predicted Normal. [From Baseline to Weeks 24 and 48]: FEV1 is the volume of air expired in 1 second in liters (L). Higher values indicate better respiratory function.
• Change in QT Interval Corrected by Fridericia (QTcF) [From Baseline to Weeks 4 and 24]: Assessment of the safety of MOL compared to placebo

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Subject must be ≥18 years of age, at the time of signing the informed consent (≥20 in Japan).
2. A serum anti-GM-CSF autoantibody test result confirming autoimmune PAP.
3. History of PAP, based on examination of a lung biopsy, bronchoalveolar lavage (BAL) cytology, or a high-resolution computed tomogram (HRCT) of the chest.
4. A diffusing capacity for carbon monoxide of 70% predicted or lower adjusted for hemoglobin (%DLCOadj) at the screening and baseline visits.
5. Change in %DLCO adj of <15% points during the screening period.
6. Demonstrated functional impairment in the treadmill exercise test (defined as a peak metabolic equivalent (MET) ≤8).
7. Willing and able to come off supplemental oxygen use prior to and during the treadmill exercise test, the DLCO assessment, and the arterial blood gas sampling.
8. Resting oxygen saturation (SpO2) >85% during 15 minutes without use of supplemental oxygen at the screening visits.
9. Male or female
10. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

    1. Male subjects: Males agreeing to use condoms during and until 30 days after last dose of trial treatment, or males having a female partner who is using adequate contraception as described below.
    2. Female subjects: Females who have been post-menopausal for >1 year, or females of childbearing potential after a confirmed menstrual period using a highly efficient method of contraception (i.e. a method with <1% failure rate such as combined hormonal contraception, progesterone-only hormonal contraception, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner, sexual abstinence*), during and until 30 days after last dose of trial treatment. Females of childbearing potential must have a negative serum pregnancy test at the screening visits, and a negative urine pregnancy test at Baseline visit (Visit 3) and must not be lactating.
11. Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
12. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures specified in the protocol as judged by the Investigator.

Exclusion Criteria:

1. Diagnosis of hereditary or secondary PAP, or a metabolic disorder of surfactant production.
2. Whole lung lavage (WLL) performed within 3 months prior to baseline.
3. Requirement for WLL at screening or baseline.
4. GM-CSF treatment within 6 months prior to baseline.
5. Treatment with rituximab within 6 months prior to baseline.
6. Treatment with plasmapheresis within 6 weeks prior to baseline.
7. Treatment with any investigational medicinal product within 5 half-lives or 3 months (whichever is longer) prior to baseline.
8. Previously randomized in this trial.
9. History of allergic reactions to GM-CSF or any of the excipients in the nebulizer solution.
10. Inflammatory or autoimmune disease of a severity that necessitates significant (e.g. more than 10 mg/day systemic prednisolone) immunosuppression.
11. Previous experience of severe and unexplained side-effects during aerosol delivery of any kind of medicinal product.
12. History of, or present, myeloproliferative disease or leukemia.
13. Apparent pre-existing concurrent pulmonary fibrosis.
14. Acute or unstable cardiac or pulmonary disease that may be aggravated by exercise.
15. Known active infection (viral, bacterial, fungal, or mycobacterial) that may affect the efficacy evaluation in the trial.
16. Physical disability or other condition that precludes safe and adequate exercise testing.
17. Any other serious medical condition which in the opinion of the Investigator would make the subject unsuitable for the trial.
18. Pregnant, planning to become pregnant during the trial, or breastfeeding woman. For France only: including as further defined by French Health Code L-1121-5.
19. For France only: Any subject considered to be "vulnerable" on account of, e.g., mental or physical disability, socio-economic situation, or subjects deprived of their liberty. For France only: including as further defined by French Health Code L1121-8-1.

Participant flow

Outcome results

• Change From Baseline in Percent (%) Predicted Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) Adjusted for Hemoglobin Concentration to Week 24 (Primary), Least squares mean, % predicted DLCO adjusted for hemoglobin: Molgramostim 9.8 (7.3 to 12.3); Placebo 3.8 (1.4 to 6.3) (p 0.0007)
• Change From Baseline in Percent (%) Predicted DLCO Adjusted for Hemoglobin Concentration (%DLCOadj) to Week 48 (Secondary), Least squares mean, Unit of Measure: % predicted DLCO adjust: Molgramostim 11.6 (8.7 to 14.5); Placebo 4.7 (1.8 to 7.6) (p 0.0008)
• Change From Baseline in St. Georges Respiratory Questionnaire (SGRQ) Total Score to Week 24 (Secondary), Least squares mean, Change from baseline units on a scale: Molgramostim -11.5 (-15.01 to -7.98); Placebo -4.9 (-8.28 to -1.52) (p 0.0072)
• Change From Baseline in SGRQ Activity Component Score to Week 24 (Secondary), Least squares mean, units on a scale: Molgramostim -13.03 (-17.58 to -8.49); Placebo -5.22 (-9.76 to -0.69) (p 0.0149)
• Change From Baseline in Exercise Capacity (EC), Expressed as Peak Metabolic Equivalents (METs) to Week 24 (Secondary), Least squares mean, Change from baseline in METS: Molgramostim 1.11 (0.76 to 1.46); Placebo 0.70 (0.34 to 1.05) (p 0.0845)
• Change From Baseline in SGRQ Total Score to Week 48 (Secondary), Least squares mean, Change from baseline units on a scale: Molgramostim -10.72 (-15.01 to -6.44); Placebo -5.85 (-9.96 to -1.74) (p 0.1046)
• Change From Baseline in SGRQ Activity From Baseline to Week 48 (Secondary), Least squares mean, Change from baseline score on a scale: Molgramostim -13.39 (-18.87 to -7.91); Placebo -7.40 (-12.72 to -2.09) (p 0.1216)
• Change From Baseline in EC, Expressed as Peak METs to Week 48 (Secondary), Least squares mean, Change from baseline in METS: Molgramostim 1.13 (0.77 to 1.49); Placebo 0.58 (0.22 to 0.93) (p 0.0234)
• Change From Baseline in Alveolar-arterial Oxygen Difference (A-aDO2) to Week 24 (All Subjects) (Secondary), Least squares mean, mmHg: Molgramostim -7.97 (-11.62 to -4.32); Placebo -3.96 (-7.48 to -0.44) (p 0.1043)
• Number of Subjects With Serious and Non-serious Adverse Events (Secondary), Number, participants: Molgramostim 69; Placebo 71
• Number of Subjects With Positive Treatment-boosted Anti Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) Antibody Titers During 24 Weeks' Treatment and During 48 Weeks' Treatment (Secondary), Count of participants, Participants: Molgramostim 28; Placebo 30
• Changes in Forced Vital Capacity (FVC) %Predicted Normal (Secondary), Mean, % FVC predicted: Molgramostim 3.2 +/- 6.20; Placebo 0.9 +/- 5.74
• Changes in Forced Expiratory Volume in One Second (FEV1) % Predicted Normal. (Secondary), Mean, %predicted normal: Molgramostim 1.2 +/- 7.08; Placebo -0.3 +/- 5.35
• Change in QT Interval Corrected by Fridericia (QTcF) (Secondary), Mean, msec: Molgramostim -2.51 +/- 10.543; Placebo 1.59 +/- 10.127

Adverse events

Time frame: Adverse events during double-blind treatment (48 Weeks)

Serious adverse events by term

Other adverse events by term

• Results publication: Trapnell BC, Inoue Y, Bonella F, Wang T, McCarthy C, Arai T, Akasaka K, Mariani F, Mogulkoc N, Song JW, Baba T, Jouneau S, Numakura T, Ocal N, Mihaltan F, Ataya A, Bendstrup E, Campo I, Carey B, Arena R, Robinson B, Fleming R, Wasfi Y, Pratt R; IMPALA-2 Trial Investigators. Phase 3 Trial of Inhaled Molgramostim in Autoimmune Pulmonary Alveolar Proteinosis. N Engl J Med. 2025 Aug 21;393(8):764-773. doi: 10.1056/NEJMoa2410542. PMID 40834301

• Study Protocol (PDF, 2024-10-09)
• Statistical Analysis Plan (PDF, 2024-04-24)

• Bruce Trapnell, MD, Principal investigator, Children's Hospital Medical Center, Cincinnati