Savara Pharmaceuticals (United States)

<b>Background:</b> Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive accumulation of surfactant material in alveoli which impairs gas exchange.¹ Currently, no outcome measures have been validated in aPAP patients for use as clinical trial endpoints. Diffusing capacity of the lung for carbon monoxide (DL_CO) is a standardized measure of pulmonary gas transfer used in clinical practice.² The phase 2 IMPALA (NCT02702180) study demonstrated improvements in DLco among aPAP patients who responded to inhaled molgramostim nebulizer solution (MOL); the estimated difference (95% CI) between MOL vs placebo (PBO) was 7.8 (2.3–13.3).¹ <b>Objective:</b> To describe the rationale for using DL_CO as the primary endpoint in IMPALA-2 (NCT04544293), a pivotal, randomized, global study of MOL administered in aPAP. <b>Results:</b> IMPALA-2, a phase 3 study, will evaluate the safety and efficacy of daily MOL (300 µg) vs PBO for 48 weeks. The favorable results from the IMPALA study in change from baseline to week 24 in DLco informed the study design of IMPALA-2.¹ DL_CO is part of the standard ERS/ATS approved lung function tests, non-invasive, and widely used in clinical practice.² DL_CO reflects the pathophysiological process of aPAP, can predict the need for rescue treatment, and is commonly used to indicate the need for the major clinical event, whole lung lavage therapy. <b>Conclusion:</b> DL_CO is a convenient, standardized, and widely-used lung function test that is directly relevant to the pathophysiology of aPAP and is considered suitable for use as the primary endpoint in IMPALA-2 for daily MOL among patients with aPAP. <b>

Methicillin-resistant Staphylococcus aureus (MRSA) has become a significant acute and chronic respiratory pathogen. While vancomycin is effective against MRSA, its relatively poor penetration into lung secretions and dose-limiting renal toxicity make it less effective in the respiratory setting. As inhaled administration of vancomycin would overcome these limitations, we developed a dry powder formulation suitable for inhalation (AeroVanc). Here, we report a phase I, single-dose, dose-escalating study aimed at demonstrating safety and tolerability of AeroVanc. In part I, 18 healthy subjects received a single dose of 16 mg, 32 mg, or 80 mg of AeroVanc. Two subjects also received a 250-mg dose of intravenous vancomycin. In part 2 of the study, 32 mg and 80 mg AeroVanc were administered to subjects with cystic fibrosis as single doses. There were no serious side effects. A small drop in forced expiratory volume in 1 s (FEV1) was observed in 3 subjects with cystic fibrosis, one of whom required salbutamol. Vancomycin was rapidly absorbed after inhalation. Peak and mean plasma concentrations of vancomycin were dose proportional. The average minimum concentration of vancomycin in sputum remained above the usual MIC values for MRSA for up to 24 h (minimum sputum concentration [Cmin], 32-mg dose = 3.05 μg/ml, 80-mg dose = 8.0 μg/ml). In conclusion, AeroVanc was well tolerated and achieved high levels in sputum with a mean systemic absorption of 49%, making it a potential therapeutic strategy for respiratory infection with MRSA.