By Marcel Veltkamp
Pulmonary Alveolar Proteinosis (PAP) is a rare lung disease characterized by accumulation of surfactant in the alveolar spaces causes by dysregulating of surfactant homeostasis, resulting in impairment of gas exchange. In more than 90% of adult PAP patients auto-antibodies against granulocyte/macrophage colony-stimulating factor (GM-CSF) can be detected (1), resulting in autoimmune PAP (aPAP). These GM-CSF auto-antibodies are polyclonal and recognize human GM-CSF with high avidity and specificity and are very effective in dysregulating surfactant homeostasis (2).
Current standard therapy of severe aPAP is whole lung lavage (WLL), a procedure in which one lung is mechanically ventilated while the other is repeatedly lavaged with warmed saline in 0.5 to 1 liter aliquots with intensive chest percussion to dissolve the accumulated protein (3). This process generally takes 4-6 hours. It is effective in most patients, however, it is required repeatedly in a significant number of patients based on continued intra-alveolar surfactant accumulation (4). Because of the complexity of the procedure and the low prevalence of aPAP, it is mostly being performed in referral centers for interstitial lung disease.
In the last two decades, therefore, an important focus of scientific research has been to develop less invasive therapies for patients with aPAP. Studies using recombinant GM-CSF subcutaneously or by nebulisation in patients with aPAP have been published with promising results (5, 6). More recent data suggest that inhalation of GM-CSF is associated with higher response rates and improved safety profile compared to subcutaneous administration of GM-CSF(6). However, no randomized controlled trial has been performed addressing the effectiveness of inhaled recombinant GM-CSF in patients with aPAP so far.
Fortunately, starting in February of this year, a multicenter trial – IMPALA – is recruiting patients with aPAP to investigate the treatment effect of inhaled molgramostim (recombinant GM-CSF) (7). This trial is a randomized, double-blind, parallel group comparison of inhaled molgramostim with placebo. It consists of a double-blind treatment period of 24 weeks followed by a 48 week observation period to investigate the long term outcomes. In literature a wide range of dose regimens is used and therefore two different doses regimens of molgramostim will be investigated in the IMPALA trial. One regimen consists of continuous administration of molgramostim 300µg once daily for 24 weeks and the other regimen will be intermittent administration (12 cycles of 7 days molgramostim 300µg once daily followed by 7 days of placebo). The placebo group will receive continuous daily treatment.
The primary endpoint in the IMPALA trial is the difference in the alveolar-arterial gradient between baseline and after 24 weeks of treatment. Key secondary endpoints are the amount of patients requiring a whole lung lavage, the time to a whole lung lavage and absolute change from baseline in Vital Capacity (%predicted) after 24 weeks of treatment.
The IMPALA trial, being the first randomized controlled trial investigating treatment with inhalation of GM-CSF, is another important step forward for patients with autoimmune PAP. The estimated study completion date is August 2018 and the results are eagerly awaited.