Investigating GM-CSF in aPAP: A Logical Replacement of a Dysfunctional Protein

Investigating GM-CSF in aPAP: A Logical Replacement of a Dysfunctional Protein

―Bruce Trapnell, M.D.

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare lung disease with no approved pharmacologic treatment options and is caused by an abnormal accumulation of surfactant sediment in the alveoli (air sacs), leading to impaired gas exchange between the lungs and blood. Throughout my career I have found that aPAP has an unpredictable clinical course which can include infection, progressive respiratory failure or even pulmonary fibrosis requiring a lung transplant. The 5-year survival rate for aPAP patients without treatment is approximately 85%, with death typically due to respiratory insufficiency or infection. The disease has a meaningful impact on patients’ quality of life as they become increasingly breathless, often with cough, sputum production, weight loss and are frequently fatigued. Additionally, they experience significantly reduced exercise capacity that can dramatically impact the simplest of daily activities, e.g., becoming winded simply walking up a flight of stairs.

Currently, there are no approved pharmacological treatment options for aPAP and, historically, whole lung lavage (WLL) has been relied upon to physically remove surfactant from a patient’s lungs. WLL is an invasive and inefficient procedure, performed under general anesthesia, and involves placing a tube in each lung and washing out the lungs to improve lung function and reduce symptoms. One lung is mechanically ventilated while the other is repeatedly filled with salt water, the chest is percussed (“clapped”) to mix the surfactant (mostly lipid) with the salt water and then drained to remove the salt water and surfactant sediment. However, since surfactant is not water soluble, WLL is not an efficient procedure; I often describe it as “like washing butter out of a sponge with a garden hose.” Due to the rarity of aPAP and the lack of randomized clinical trials, there are no formal guidelines for performing WLL in patients with the disease, and the procedure hasn’t advanced substantially since it was introduced four decades ago. The frequency and timing of WLL is decided on a case-by-case basis based on blood oxygenation, lung function, symptoms and impact to quality of life. The need for anesthesia, coupled with the invasive nature of the procedure, means that WLL should only be performed in specialized centers using a skilled and experienced multidisciplinary care team. It is important to note that while WLL is currently used to treat patients with aPAP, WLL fails to address the underlying pathophysiology that drives surfactant accumulation. Therefore, patients continue to experience symptomatic deterioration due to disease progression between procedures – it is truly a rollercoaster ride of improvement and decline.

Based on research advances over several decades, the mechanism that causes aPAP is now well understood. Normally, surfactant is composed of polar or charged lipids (mostly phospholipids), neutral lipids (mostly cholesterol), and surfactant proteins (surfactant A-D) in ratio of about 80%, 10%, 10%, respectively. Surfactant comprises a thin layer lining the alveoli that functions by reducing surface tension and, thereby, preventing the alveoli from collapsing (as a balloon does when the untied end is released). The surfactant layer must be thick enough to reduce surface tension, yet sufficiently thin to permit oxygen to diffuse from the alveoli into the blood coursing through the capillaries that surround the alveoli. Excess surfactant is continuously removed by alveolar macrophages, which help keep this layer sufficiently thin to permit good gas exchange.
Granulocyte macrophage-colony stimulating factor (GM-CSF) is a small protein molecule required by alveolar macrophages to stimulate normal differentiation (maturation), and one of its functions includes removal of excess surfactant from the lungs. GM-CSF is also important for controlling the host defense functions of alveolar macrophages and blood neutrophils (a major white blood cell type required for fighting infections). Recently, pulmonary GM-CSF was found to control the size of the alveolar macrophage population in the lungs. In summary, GM-CSF is a molecule critical to surfactant homeostasis, alveolar stability, lung function, and host defense – a critical pulmonary hormone.

In patients with aPAP, the abnormal development of a high level of neutralizing GM-CSF autoantibodies blocks GM-CSF signaling to alveolar macrophages, which impairs alveolar macrophage development and function, and results in progressive surfactant accumulation. In essence, aPAP patients are drowning in their own surfactant.
Autoimmune PAP is a specific disease belonging to a family of distinct diseases collectively referred to as PAP syndrome (which is characterized by the accumulation of surfactant). Autoimmune PAP represents about 90% of all patients with PAP syndrome, and the prevalence of aPAP is estimated to be approximately 7 patients per million people in the U.S. Similar numbers have been reported elsewhere in the world, and aPAP does not appear to be more prevalent across specific geographies or ethnic groups. However, as we have seen with other orphan diseases, increased awareness can lead to better testing and shorten the time required for an accurate diagnosis. A good example of this comes from Japan where they have a more centralized approach to diagnosing and treating aPAP. Over the last seven years, the Japanese have seen a consistent increase in patients being diagnosed with the disease and they now believe the prevalence rate could be three times the original estimate of 7 per million. This increase in newly diagnosed cases could, perhaps, mean that the true incidence of aPAP is being unmasked through increased awareness and use of appropriate diagnostic methods.

A diagnosis of PAP is suggested by a clinical history of progressive breathlessness of insidious onset, with or without cough and fatigue, and a characteristic radiographic appearance on the chest CT referred to as “crazy paving.” PAP syndrome is often diagnosed by bronchoscopy and bronchoalveolar lavage, which reveals the characteristic opaque milky fluid, and microscopic examination of lavage cytology. Additionally, microscopic examination of a transbronchial or surgical lung biopsy can be used to identify the presence of PAP. However, neither of these methods are capable of identifying the specific PAP-causing disease, biopsy samples may produce false negative results, and both are invasive procedures. Research advances have led to the development of a highly effective, simple blood test that can diagnose aPAP with 100% sensitivity and 100% specificity and can easily distinguish aPAP from other PAP-causing diseases. With a push for wider adoption of this diagnostic test, we could see prevalence rates rise due to more accurate and simplified testing, as well as increased awareness of the disease.

Research has demonstrated that treatment with inhaled GM-CSF can improve the clinical signs and symptoms of aPAP. This makes perfect sense as it’s a logical replacement of a protein that has been neutralized by autoantibodies. In published studies, inhaled GM-CSF was effective no matter how it was measured, including improved oxygenation and patient-reported outcomes. Restoring normal GM-CSF function in the lungs through inhaled GM-CSF could open up new therapeutic possibilities for physicians and patients as they work together to manage aPAP. While there is some off-label use of GM-CSF in the U.S., I have limited such use in my own practice for several reasons. First, the cost makes it unaffordable without insurance reimbursement and the effort to get off-label use reimbursed through insurance is quite difficult. Secondly, off-label GM-CSF is not paired with a nebulizer so it’s difficult to determine the proper dosing and to know how much of the drug is actually getting deposited into the lungs. Finally, there is some risk involved when prescribing a medication off-label – for both doctor and patient. However, as soon as an approved GM-CSF therapy for aPAP is on a payer’s formulary, I believe physicians will prescribe it broadly as first-line therapy and it will replace WLL. To be clear, I anticipate that there are certain clinical settings where WLL will continue to be used, for example, in newly diagnosed individuals. Frequently, by the time a patient is diagnosed, the accumulation of surfactant is so significant that the patient is in desperate need of acute therapeutic intervention. Eventually, I believe that WLL will be offered less and less and primarily only to get newly diagnosed patients out of immediate trouble.

I am very hopeful about Savara’s Phase 3 IMPALA clinical study of Molgradex, an inhaled GM-CSF administered with the PARI eFlow nebulizer, and currently serve as the program’s lead Principal Investigator in the U.S. Savara is assessing the potential for Molgradex to restore oxygen exchange from lungs to blood, improve exercise capacity, reduce the need for WLL, and improve patient quality of life. While the results of the study are pending (top line data are expected in June 2019), if successful, Molgradex would be the first approved pharmacological treatment for patients with aPAP. Given that Savara’s Molgradex is a slightly more active drug than the off-label GM-CSF being used, with a higher dose regimen than what was used in most of the previously published studies, and is coupled with a more efficient nebulizer, I am very optimistic about the product eventually gaining FDA approval.
The aPAP patient community is waiting for this therapy and I am hopeful that it could become a first-line therapy for patients seeking better treatment options. It is my belief that there will be a mass adoption of this therapy, if approved. I know I will prescribe it and I believe others will too.

Bruce Trapnell, M.D.
Scientific Director, PAP Foundation
Director, Transitional Pulmonary Science Center
Co-Director, Rare Lung Diseases Clinical Research Consortium
Attending Physician, Cincinnati Children’s Hospital Medical Center
Professor of Medicine and Pediatrics, University of Cincinnati College of Medicine


Savara cautions you that statements herein that are not a description of historical fact are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements may be identified by the use of words referencing future events or circumstances such as “expect,” “intend,” “plan,” “anticipate,” “believe,” and “will,” among others. Such statements include, but are not limited to, the belief that as soon as an approved GM-CSF therapy for aPAP is on a payer’s formulary, physicians will prescribe it broadly as first-line therapy and it will replace WLL, the belief that WLL will be offered less and less and primarily only to get newly diagnosed patients out of immediate trouble, that if IMPALA is successful, Molgradex would be the first approved pharmacological treatment for patients with aPAP, optimism about Molgradex eventually gaining FDA approval, statements regarding being hopeful that Molgradex could become a first-line therapy for patients seeking better treatment options, the belief that there will be a mass adoption of Molgradex if it is approved, and the belief that doctors will prescribe Molgradex for aPAP. Savara may not actually achieve any of the matters referred to in such forward-looking statements, and you should not place undue reliance on these forward-looking statements. These forward-looking statements are based upon Savara’s current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks and uncertainties associated with the outcome of ongoing clinical trials for our product candidates, the ability to project future cash utilization and reserves needed for contingent future liabilities and business operations, the availability of sufficient resources for Savara’s operations and to conduct or continue planned clinical development programs, the ability to obtain the necessary patient enrollment for our product candidates in a timely manner, the timing and ability of Savara to raise additional equity capital as needed to fund continued operations, the ability to successfully develop our product candidates, and the risks associated with the process of developing, obtaining regulatory approval for and commercializing drug candidates that are safe and effective for use as human therapeutics. All forward-looking statements are expressly qualified in their entirety by these cautionary statements. For a detailed description of our risks and uncertainties, you are encouraged to review our documents filed with the SEC including our recent filings on Form 8-K, Form 10-Q and Form 10-K. You are cautioned not to place undue reliance on our forward-looking statements herein, which speak only as of May 8, 2019 which is the date on which they were made. Savara undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after such date, except as may be required by law.