Savara Inc. is a clinical-stage specialty pharmaceutical company focused on the development and commercialization of novel therapies for the treatment of serious or life-threatening rare respiratory diseases. Savara’s strategy involves expanding its pipeline of potentially best-in-class products through indication expansion, strategic development partnerships and product acquisitions, with the goal of becoming a leading company in its field. Savara’s management team has significant experience in orphan drug development and pulmonary medicine, in identifying unmet needs, developing and acquiring new product candidates, and effectively advancing them to approvals and commercialization.

Pulmonary Alveolar Proteinosis (PAP) is a rare lung disease, which affects approximately 7 persons in a million people. It is characterised by the build-up of grainy material in the air sacs (alveoli) in the lungs. The grainy material consists of proteins and lipids from lung surfactant – an important substance that coats the inside of the air sacs to prevent the lungs from collapsing. The air sacs need to be inflated for the lungs to absorb the oxygen that the patient breathes and transfer it to the blood circulation. The body continuously produces new active surfactant. In healthy lungs the old, inactivated surfactant is digested by immune cells called alveolar macrophages. They are the dustmen or garbage collectors of the body and they have a very important task of keeping the alveoli clean. In PAP lungs, however, the macrophages fail to clean the air sacs. Consequently, the old surfactant material builds up gradually in the lungs and eventually fills the alveoli causing the patient to feel breathless. Scientific research shows that the macrophages need to be stimulated by the GM-CSF protein in order to function. In PAP lungs, however, the GM-CSF protein is either inactivated or defective, rendering the macrophages or dustmen unable to perform their cleaning tasks. The patient is commonly a man in early middle age who experiences increasing breathing difficulty, first with exertion, later at rest while developing a cough. There may be episodes of fever, chest pain, or coughing blood, especially if secondary lung infection develops. The best available treatment today is periodic whole lung lavage (WLL), i.e. washing out the lungs under general anesthesia. This requires admission to intensive care, which is an invasive and inconvenient procedure that can only be conducted effectively and safely by highly experienced physicians at a few specialist sites.
NTM lung infection is a rare and serious lung disorder associated with increased rates of morbidity and mortality. Nontuberculous mycobacteria are naturally-occurring organisms and NTM lung infection can occur when an individual inhales the organism from their environment and develop a slowly progressive and destructive lung disease. NTM lung infection is typically characterized by cough, fatigue, and weight loss. NTM infections often become chronic and require long courses of multiple antibiotics, and despite the aggressive treatment regimens, treatment failure rates are high, and recurrence of infection common. Chronic NTM lung infection can have a significant impact on quality of life. There are approximately 50,000 to 80,000 individuals affected by NTM lung infection in the U.S, the most common types involving Mycobacterium avium complex (MAC), and Mycobacterium abscessus. There have been few advancements in new systemic treatments for NTM lung infection. However, in a recent Phase 3 clinical trial by Insmed (NASDAQ: INSM), local delivery of an inhaled form of amikacin directly to the lung was shown to be effective in approximately one third of treatment refractory patients with pulmonary MAC infection, suggesting administration of high local concentrations of drug directly at the site of infection provides an attractive new avenue to improve clinical outcomes in this and other difficult to treat chronic lung infections.

Nontuberculous mycobacterial lung infections are a considerable therapeutic challenge due to the unique ability of these bacteria to evade the normal killing mechanisms of alveolar macrophages, a type of immune cells responsible for killing bacteria in the lungs. There is increasing scientific literature suggesting that GM-CSF plays an important role in enhancing the ability of macrophages to clear mycobacteria. For instance, GM-CSF knock out mice inoculated with Mycobacterium abscessus develop a chronic lung disease resembling human chronic infection, whereas wild type mice with intact GM-CSF production typically clear the bacteria quickly, and fail to develop chronic infection. In animal studies, GM-CSF has been shown to kill NTM with similar efficacy compared to commonly used NTM antibiotics, and the simultaneous use of GM-CSF with antibiotics can further improve the antibacterial effect of either GM-CSF or antibiotics given alone. In two thus far unpublished clinical case reports, inhaled GM-CSF was shown to eradicate or dramatically reduce the bacterial burden in patients with refractory M. abscessus lung infection, which suggests the promising animal data may be translatable to humans, and that the potential therapeutic role of GM-CSF in NTM lung infection warrants more intensive investigation. Among the various NTM species, M. abscessus is a particularly challenging clinical problem, being one of the most resistant organisms to antibiotics. Importantly, GM-CSF is not an antibiotic, but instead targets the human immune response, not the bacteria directly, thus avoiding the increasing problem of antibiotic resistance.


Frontal chest radiograph in patient with cystic fibrosis

There are approximately 30,000 people living with cystic fibrosis in the U.S. Cystic fibrosis is a life-shortening genetic disease characterized by thick, sticky mucus in the lungs and chronic lung infections resulting in gradual loss of lung function. The most prevalent lung pathogen in cystic fibrosis patients is Pseudomonas aeruginosa, which is commonly treated using inhaled antibiotics. In recent years, methicillin-resistant Staphylococcus aureus (MRSA), a bacterium that is resistant to conventional antibiotics (1), has become increasingly common, with a prevalence of almost 30% of the U.S. cystic fibrosis patient population. Recent publications indicate that cystic fibrosis patients with chronic MRSA infection have more hospitalizations, faster decline in lung function, and reduced life expectancy. (2,3,4) [1] Gorwitz RJ et al. Journal of Infectious Diseases. 2008:197:1226-34. [2] Prevalence and impact on FEV1 decline of chronic methicillin-resistant Staphylococcus aureus (MRSA) coloniation in patients with Cystic Fibrosis: A single-center case control study of 165 patients. Vanderhelst E, De Meirleir L, Verbanck S. et al. s.l. : J Cystic Fibrosis, 2012, Vol. 11, pp. 2-7. [3] Persistent Methicillin-resistant Staphylococcus aureus and Rate of FEV1 Decline in Cystic Fibrosis. Dasenbrook EC, Merlo CA, Diener-West M, et. al. s.l. : Am J Respir Crit Care Med, 2008, Vol. 178, pp. 814-821. [4] Elliott C. Dasenbrook; William Checkley; Christian A. Merlo; Michael W. Konstan; Noah Lechtzin; Michael P. Boyle. Association Between Respiratory Tract Methicillin-Resistant Staphylococcus aureus and Survival in Cystic Fibrosis. JAMA, 2010; 303 (23): 2386-2392.

Heart failure with preserved ejection fraction (HFpEF) is a condition that affects millions in the U.S. and for which no proven therapeutic agent is available. Patients with HFpEF have a form of congestive heart failure the prevents a normal amount of blood to be pumped from the heart’s left ventricle and typically experience general fatigue, shortness of breath caused by exercise.
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