molgramostim nebulizer solution expanded access program protocol

Conditions: Autoimmune Pulmonary Alveolar Proteinosis

Summary: autoimmune pulmonary alveolar proteinosis (apap) is a rare disorder in which a material called surfactant builds up in the lungs and makes it hard to breathe. in addition to shortness of breath, people with apap can experience persistent cough, overwhelming fatigue, unintentional changes in weight, chest or back pain, suddenly feeling out of shape, and general discomfort. currently, there are no approved medications for apap in the united states, but the symptoms of apap can be treated with whole lung lavage (wll). wll is an invasive procedure that temporarily removes surfactant, and it can result in serious consequences like trauma to the lung, a collapsed lung, and prolonged requirement for artificial ventilation. savara is studying an investigational drug called molgramostim nebulizer solution to see if it activates the cells that help clear surfactant from the lungs, which improves oxygen transfer from the lungs to the bloodstream. molgramostim nebulizer solution is administered by inhalation using a hand-held nebulizer. in clinical trials, molgramostim nebulizer solution has shown improvements in gas exchange and patient reported outcomes. this expanded access program will make molgramostim nebulizer solution available to adult patients with diagnosed apap. access must be obtained through the treating physician. patients will dose molgramostim nebulizer solution 300 micrograms (mcg) once daily and be followed by their physician every 3 months to assess their clinical status and report any adverse events.

autoimmune pulmonary alveolar proteinosis (apap) is a rare disease mediated by autoantibodies targeting granulocyte macrophage colony-stimulating factor (gm-csf), resulting in malfunctioning macrophages with impaired surfactant catabolism. the latter causes accumulation of surfactant in the alveoli, which has a negative impact on gas exchange between lung and blood. the clinical course of autoimmune pap varies among patients with continuously slowly progressive disease in most patients, spontaneous improvement in a small percentage (5-7%), and rapid progression and/or pulmonary fibrosis, respiratory failure, and death in others. the most common cause of death is respiratory failure followed by secondary pulmonary bacterial infections. estimated 5-year mortality rates vary between 10-30%, with overall disease-specific survival rates at 5 years exceeding 80%. there are currently no approved pharmacological treatments for apap in most of the world. whole lung lavage (wll) is the primary treatment option currently available for most apap patients. however, its invasive nature, limited access, and the variable effect of wlls due to lack of standardization emphasize that there is an unmet need for a non-invasive, safe and well-tolerated, easily accessible and effective treatment for apap patients. the rationale for treating apap patients with molgramostim nebulizer solution is based on the capacity of gm-csf to promote differentiation and mobilization of different myeloid leukocyte subsets including neutrophils, tissue macrophages/dendritic cells or their circulating precursors. it is crucially involved in anti-microbial pulmonary host defense and ameliorates lung injury by increasing the size and activation of the alveolar macrophage pool. gm-csf also contributes to the proliferation of megakaryocytic and erythroid progenitors and plays a key role in surfactant homeostasis, by maturation of alveolar macrophages. molgramostim is a non-glycosylated recombinant human granulocyte macrophage colony stimulating factor (rhgm-csf) produced by using recombinant dna technology via a bacterial (e. coli) expression system. molgramostim is formulated in a sterile nebulizer solution (molgramostim nebulizer solution) which is supplied in vials containing 300 µg of molgramostim in 1.2 ml solution and is administered by inhalation via an investigational eflow nebulizer system (pari pharma gmbh). results of a completed randomized, placebo-controlled clinical trial support the safety, tolerability, and efficacy of inhaled molgramostim nebulizer solution as a treatment for autoimmune pap patients.

Eligibility criteria:
inclusion criteria: eligible patients must: 1. be ≥18 years of age at the time of signing the informed consent. 2. agree to use a highly effective form of contraception (see section 3.5). 3. have a positive serum anti-granulocyte macrophage colony-stimulating factor (gm csf) autoantibody test result confirming apap. 4. have a history of pulmonary alveolar proteinosis (pap), based on examination of a lung biopsy, bronchoalveolar lavage (bal) cytology, or a high-resolution computed tomogram (hrct) of the chest. 5. have at least one symptom of apap, including but not limited to dyspnea (at rest or with exertion), cough, or fatigue. 6. be capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (icf) and in this protocol. 7. be willing and able to comply with the visit schedule and treatment plan specified in the protocol, as judged by the physician. exclusion criteria: eligible patients must not: 1. have a diagnosis of hereditary or secondary pap, or a metabolic disorder of surfactant production. 2. require a whole lung lavage (wll) at the time of screening (patient may be eligible 1 week post wll). 3. have received gm-csf treatment within 1 month prior to the screening visit. 4. have been treated with any investigational product within 5 half-lives or 3 months (whichever is longer) prior to the screening visit. 5. have a history of allergic reactions to gm-csf or any of the excipients in the nebulizer solution. 6. be using significant (e.g., more than 10 mg/day systemic prednisolone) immunosuppression. 7. have a history of severe and unexplained side effects during aerosol delivery of any medicinal product. 8. have a history or current diagnosis of a myeloproliferative disease or leukemia. 9. have any other medical condition which in the opinion of the physician would make the patient unsuitable for treatment with molgramostim nebulizer solution. 10. be pregnant or breastfeeding, or planning to become pregnant during treatment with molgramostim nebulizer solution.

Keywords: surfactant accumulation autoimmune alveolar proteinosis gm-csf