Background SPR206 is a novel intravenously (IV)-administered next-generation polymyxin being developed for the treatment of multi-drug resistant (MDR) Gram-negative (GN) infections. A Phase 1 bronchoalveolar lavage (BAL) study was conducted to evaluate SPR206 safety and PK in plasma and pulmonary matrices (ELF and AM) in healthy volunteers. Methods Subjects received 100 mg SPR206 administered intravenously over 1 h q8h for 3 consecutive doses. Blood samples were collected pre-dose (second and third dose) and at 2, 3, 4, 6, and 8 h after the start of the last dose. Each subject underwent one standardized bronchoscopy with BAL at 2, 3, 4, 6 or 8 hours after the start of the third IV infusion. Concentrations of SPR206 in plasma, BAL, and cell pellet were measured with a validated LC-MS/MS assay. Plasma, ELF, and AM PK parameters were determined by noncompartmental analysis. SPR206 AUC0–8 in ELF and AM were calculated using the mean concentration values at the BAL sampling times. SPR206 AUC0–8 ratios of ELF and AM to unbound plasma were determined using plasma protein binding value of 8.6%. Results Thirty-four subjects were enrolled and completed the study and 30 of 34 completed bronchoscopy. The mean SPR206 Cmax concentrations in plasma, ELF, and AM were 4395.0, 735.5, and 860.6 ng/mL, respectively. Mean AUC0-8 h values in plasma, ELF, and AM concentrations were 20120.7, 4859.8, and 6026.4 ng*h/mL, respectively--leading to a free ELF to plasma concentration ratio of 0.264 and free AM to plasma ratio of 0.328. Importantly, mean concentrations of SPR206 in the ELF achieved lung exposures above its minimum inhibitory concentration for the targeted gram-negative pathogens for the entire 8-hour dosing interval. Figure 1 displays the mean (±SD) SPR206 total and unbound plasma, ELF, and AM concentrations at the BAL sampling times. Overall, SPR206 was well tolerated; 22 subjects (64.7%) experienced at least 1 TEAE, mostly mild with a few moderate. The most frequently reported TEAEs were oral paresthesia [10 subjects (29.4%)] and nausea [2 subjects (5.9%)], which were reversible. Conclusion This study demonstrates pulmonary penetration of SPR206 and supports further development of SPR206 for the treatment of patients with pneumonia caused by MDR GN infections. Figure 1.Mean (±SD) plasma (total and unbound), epithelial lining fluid (ELF), and alveolar macrophage (AM) concentrations of SPR206 in healthy adult subjects. This study was conducted in collaboration with, and with financial support from, the United States Department of Defense (Award No. W81XWH1910295). Disclosures Keith A. Rodvold, PharmD, Spero Therapeutics: Advisor/Consultant|Spero Therapeutics: Honoraria Justin Bader, n/a, Spero Therapeutics: Employee Vipul K. Gupta, Ph.D., Spero Therapeutics: Employee Troy Lister, Ph.D., Spero Therapeutics: Employee Praveen Srivastava, Ph.D., Spero Therapeutics: Employee Jon Bruss, M.D., Spero Therapeutics: Employee.

SPR206 is a next-generation polymyxin being developed for the treatment of multidrug-resistant (MDR) Gram-negative infections. This Phase 1 bronchoalveolar lavage (BAL) study was conducted to evaluate SPR206’s safety and pharmacokinetics in plasma, pulmonary epithelial lining fluid (ELF), and alveolar macrophages (AM) in healthy volunteers.

Background The CDC lists multidrug-resistant PA as a Serious Threat pathogen causing 32,200 hospital infections and 2,700 deaths in the US in 2017. PA resistance is frequent with antibiotic monotherapies. SPR206 is a next generation polymyxin that, in a first in human study, was generally safe and well tolerated at the potential therapeutic dose of 100 mg IV Q8h. The aim of this study was to quantify the dose-range PA killing activity of SPR206 monotherapy in a hollow fiber infection model (HFIM) and to assess if the combination of SPR206 and MEM more effectively reduces bacterial burden and prevents development of resistance than either drug alone. Methods Agar dilution MICs and mutation frequencies (MFs) for SPR206, PMB, & MEM were performed for PA ATCC 27853. A 10-day HFIM dose range study simulating the free PK profiles for SPR206 (50 – 600 mg IV Q8h) quantified PA killing and possible regrowth. A HFIM study compared single vs combination SPR206 100 mg IV Q8h over 1h and MEM 2g IV Q8h over 1h regimens for enhanced PA killing and resistance suppression. Results The SPR206, PMB, & MEM MICs were 0.5, 0.5, and 0.25 mg/L, respectively. The MFs for SPR206 and PMB to 3x, 5x and 8x MIC were -6.2, -6.9, & -7.7 log CFU and -5.3, -6.4, & -7.7 log CFU, respectively. The MF for 3x MIC of MEM was -6.8 log CFU. In a dose-range HFIM, simulated regimens for 50 – 600 mg IV Q8h showed a dose-response effect, with 2.9 – 7.3 log CFU/mL reductions in PA seen at 5h. All regimens had regrowth by isolates with SPR206 MICs of 1 – 8 mg/L. In a HFIM study simulating the SPR206 and MEM clinical regimens, alone and in combination, SPR206 alone killed 5 log CFU/mL of PA at 5h, followed by regrowth. MEM alone killed 3.5 log CFU/mL of PA at 5h, with maximum kill seen on Day 4, followed by regrowth. SPR206 plus MEM killed 0.8 log CFU/mL more PA at 5h vs SPR206 alone and had undetectable PA counts by day 4. Combination therapy prevented regrowth (see figure). Conclusion Conclusions: SPR206 (100 mg IV Q8h) killed 5 log CFU/mL of PA at 5h, but regrowth ensued. SPR206 plus MEM produced 0.8 log CFU/mL more killing of PA at 5h. The killing activity of the 2-drug regimen combined with its resistance prevention effect resulted in undetectable PA counts by Day 4 of treatment. Disclosures Arnold Louie, MD, Curza, Inc.: Grant/Research Support|Prokaryotics: Grant/Research Support|Spero Therapeutics: Grant/Research Support Nicole Cotroneo, B.S., Spero Therapeutics: Employee|Spero Therapeutics: Stocks/Bonds Weiguo Liu, M.D., Spero Therapeutics: Grant/Research Support David Brown, M.B.A., Curza, Inc.: Grant/Research Support|Prokaryotics: Grant/Research Support|Spero Therapeutics: Grant/Research Support Jenny Myrick, B.S., Spero Therapeutics: Grant/Research Support George Drusano, M.D., Curza: Advisor/Consultant|Curza: Grant/Research Support|Prokaryotics: Grant/Research Support|Spero Therapeutics: Grant/Research Support.