Probiomed · CSF2RA · Recombinant Proteins
molgramostim is a recombinant proteins developed by Probiomed. It is approved for therapeutic indications via injectable (others).
| Brand Names | Gramal |
| Company | Probiomed |
| Drug Class | Recombinant Proteins |
| Molecular Target | CSF2RA |
| Route | Injectable (Others) |
| Status | Approved |
molgramostim acts on 1 molecular target:
| CSF2RA | colony stimulating factor 2 receptor subunit alpha (CD116, CSF2RX) |
molgramostim is developed for 1 unique indication across 1 therapeutic area.
| Therapeutic Area | Condition | Phase |
|---|---|---|
| Blood and lymphatic system disorders | Bone marrow disorder | ✓ Approved |
McCarthy Cormac C, Bonella Francesco F, Inoue Yoshikazu Y, Trapnell Bruce C BC et al.
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.
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.
McCarthy Jack J, Boyle Niamh N, McCarthy Cormac C
Autoimmune Pulmonary Alveolar Proteinosis (aPAP) is a rare disease characterized by myeloid cell dysfunction, abnormal pulmonary surfactant accumulation, and innate immune deficiency. Pathogenesis is driven by GM-CSF neutralizing autoantibodies (GMAbs) present in high titer in serum and bronchoalveolar lavage fluid (BALF) of patients. GM-CSF is a cytokine and a hematopoietic growth factor produced by a variety of cells. In the lungs, GM-CSF regulates surfactant homeostasis and lung host defense through innate immune function. Whole lung lavage (WLL) is the current first line therapy for aPAP. It is a procedure in which excessive surfactant is mechanically removed from the alveoli. Pathogenesis-driven treatment with GM-CSF augmentation has been investigated over the last two decades with recombinant GM-CSF (rGM-CSF). Molgramostim and sargramostim are rGM-CSF which can be self-administered at home by patients with aPAP either subcutaneously or using a handheld nebulizer. In Phase II and III studies of adults with aPAP, daily administration of inhaled molgramostim resulted in greater improvements in pulmonary gas transfer and functional health status than placebo, with similar rates of adverse events. In all clinical studies to date, rGM-CSF has shown a favorable safety profile with no dose limiting toxicity. This supports the application of inhaled rGM-CSF for the treatment of aPAP and the possibility of WLL as a rescue therapy.
Trapnell Bruce C BC, Carey Brenna C BC, Robinson Brian R BR
Inhaled molgramostim, a form of recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF), is a promising investigational pharmacotherapy for autoimmune pulmonary alveolar proteinosis (aPAP); however, its pharmacology in healthy subjects has not been reported. This randomised, double-blind, placebo-controlled, single-centre, phase 1 clinical trial assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled molgramostim in healthy adults in single ascending dose (SAD) and multiple ascending dose (MAD) studies: one 150, 300 or 600 µg administration or six consecutive daily 300 or 600 µg administrations with evaluations over 28 or 34 days, respectively. The primary endpoint was safety, which was evaluated based on the number and severity of treatment-emergent AEs following single and multiple inhaled doses of molgramostim. 42 subjects were enrolled including 18 in the SAD study and 24 in the MAD study; all completed the study. Inhaled molgramostim in healthy people was well tolerated and no dose-limiting safety concerns or anti-drug antibody formation were observed in either study. GM-CSF was measurable in serum 30 min after administration of inhaled molgramostim, peaked at 2 hours for all three doses and had an elimination half-life of 1.7±0.0 to 5.9±0.9 hours in the SAD and MAD studies. Systemic GM-CSF exposure was non-linear in both the SAD and MAD studies. Inhaled molgramostim caused a rapid increase in white blood cells (WBC) counts and leucocyte subsets that normalised by 8 hours (SAD) or 15-21 days (MAD). Fractional exhaled nitric oxide remained within the normal range at all doses but was numerically, but not significantly, increased at the 600 μg dose. In healthy people, inhaled molgramostim was well-tolerated and resulted in systemic exposure at picogram levels, which had the expected PD effects on blood leucocyte levels that mostly remained within normal ranges. NCT02468908; EudraCT No. 2013-001687-32.
Jouneau Stéphane S, Chauvin Pierre P, Lederlin Mathieu M, Painvin Benoît B et al.
Pulmonary alveolar proteinosis is suspected when a "crazy paving" pattern is observed on a chest CT scan. This diagnosis is confirmed by the presence of eosinophilic extracellular material that shows positive staining with Periodic Acid Schiff on bronchoalveolar lavage samples. The autoimmune form of pulmonary alveolar proteinosis is confirmed by detecting anti-granulocyte-macrophage colony-stimulating factor antibodies in the patient's serum. The historical first-line treatment for autoimmune pulmonary alveolar proteinosis is whole lung lavage, which should only be performed in expert centers. It remains the preferred treatment for patients experiencing respiratory failure, especially at the time of diagnosis. Inhaled granulocyte-macrophage colony-stimulating factor supplementation with molgramostim or sargramostim is now considered a first-line treatment in the international guidelines for autoimmune pulmonary alveolar proteinosis, following the positive results of recent randomized placebo-controlled studies. Rituximab and plasmapheresis can be prescribed as third- and fourth-line treatments, respectively. Lung transplantation may be considered for eligible patients experiencing terminal respiratory failure. A deeper understanding of the pathogenesis of autoimmune pulmonary alveolar proteinosis has opened up new therapeutic avenues, such as the use of PPARγ agonists or statins.
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