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Session - 036 FRIDAY - 82 The Antibacterial Activity of Sulbactam and the Novel b-lactamase Inhibitor ETX2514 Combined with or Against Recent Clinical Isolates of baumannii and S. McLeod1, B. Roth2, R. Flamm2, M. Huband2, J. Mueller1, R. Tommasi1, M. Perros1 and A. Miller1 Entasis Therapeutics, 1 2 1-781-810-0120, Entasis Therapeutics, Waltham, MA and JMI Laboratories, North Liberty, IA, USA www.entasistx.com

Abstract MIC Distributions of ETX2514 Combinations against 608 Geographically Diverse A. baumannii MIC Distributions of ETX2514 Combinations against 602 Geographically Diverse P. aeruginosa

Background Number (cumulative %) of isolates inhibited at MIC (mg/L) Number (cumulative %) of isolates inhibited at MIC (mg/L) ETX2514 is a novel, diazabicyclooctenone inhibitor of serine β-lactamases that 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 > 32 Drug 0.03 0.06 0.12 0.25 0.5 1 2 4 8 16 32 > 32 restores β-lactam activity against multidrug-resistant Gram negative . 0 13 126 6 19 12 8 11 9 44 360 0 3 8 54 321 57 21 47 59 10 22 IPM IPM ETX2514 is more potent and has a broader spectrum of inhibition than the 0.0% 2.1% 22.9% 23.8% 27.0% 28.9% 30.3% 32.1% 33.6% 40.8% 100.0% 0.0% 0.5% 1.8% 10.8% 64.1% 73.6% 77.1% 84.9% 94.7% 96.3% 100.0% recently approved related β-lactamase inhibitor, . ETX2514 IPM- 1 3 58 109 23 32 57 97 100 70 47 11 25 10 56 342 68 54 15 9 4 1 17 combined with sulbactam is currently in clinical development for the treatment IPM-ETX2514 1 97.0% ETX2514 0.2% 0.7% 10.2% 28.1% 31.9% 37.2% 46.5% 62.5% 78.9% 90.5% 98.2% 100.0% 4.2% 5.8% 15.1% 71.9% 83.2% 92.2% 94.7% 96.2% 96.8% 97.2% 100.0% of Acinetobacter baumannii infections. We sought to determine the relative 0 4 62 53 23 21 13 3 18 47 364 IPM-ETX2514- 28 6 59 343 67 52 15 9 4 1 17 potency of imipenem or meropenem with and without sulbactam-ETX2514 1 97.0% MEM SUL against recent, geographically diverse Pseudomonas aeruginosa and A. 0.0% 0.7% 10.9% 19.6% 23.4% 26.8% 28.9% 29.4% 32.4% 40.1% 100.0% 4.7% 5.6% 15.4% 72.4% 83.6% 92.2% 94.7% 96.2% 96.8% 97.2% 100.0% 11 29 55 132 104 69 54 42 27 42 15 22 baumannii isolates. MEM- 0 4 21 69 55 33 78 107 87 93 47 14 MEM 1.8% 6.6% 15.8% 37.7% 55.0% 66.4% 75.4% 82.4% 86.9% 93.9% 96.3% 100.0% Methods ETX2514 0.0% 0.7% 4.1% 15.5% 24.5% 29.9% 42.8% 60.4% 74.7% 89.9% 97.7% 100.0% 0 11 67 49 37 58 115 138 133 57 52 128 113 61 38 48 30 30 19 11 15 Approximately 600 P. aeruginosa and 600 A. baumannii isolates collected SUL MEM-ETX2514 during 2013, 2014 and 2015 from geographically diverse medical centers in the 0.0% 1.8% 12.8% 20.9% 27.0% 36.5% 55.4% 78.1% 100.0% 9.5% 18.1% 39.4% 58.1% 68.3% 74.6% 82.6% 87.5% 92.5% 95.7% 97.5% 100.0% United States, Europe, Latin America and the Asia-Pacific region were chosen SUL- 0 1 4 55 178 200 129 31 4 4 1 1 MEM-ETX2514- 59 52 121 131 48 38 51 29 28 20 10 15 for testing. Susceptibility testing was performed according to CLSI guidelines, ETX2514 0.0% 0.2% 0.8% 9.9% 39.1% 72.0% 93.3% 98.4% 99.0% 99.7% 99.8% 100.0% SUL 9.8% 18.4% 38.5% 60.3% 68.3% 74.6% 83.1% 87.9% 92.5% 95.8% 97.5% 100.0%

and data analysis was performed using CLSI breakpoint criteria. SUL- MIC90 value is highlighted. ETX2514 was tested at a fixed concentration of 4 mg/L. Sulbactam was added at a fixed concentration of 4 mg/L. 291 10 19 50 91 85 49 6 4 2 0 1 ETX2514- Results 47.9% 49.5% 52.6% 60.9% 75.8% 89.8% 97.9% 98.8% 99.5% 99.8% 99.8% 100.0% IPM Sulbactam plus ETX2514 (fixed at 4 mg/L) was highly active against the A. -Imipenem-ETX2514 was highly active against P. aeruginosa -Meropenem-ETX2514 combinations were less active against P. aeruginosa SUL- baumannii isolates, with MIC50/90 values of 1/2 mg/L, corresponding to 93.3% 237 14 20 60 79 120 55 14 6 2 0 1 -92% of isolates were inhibited by 1 mg/L imipenem-ETX2514 -Addition of sulbactam (fixed at 4 mg/L) did not improve the MIC90 of either ETX2514- of strains inhibited at ≤2 mg/L. A total of 28.9% and 26.8% of isolates were 39.0% 41.3% 44.6% 54.4% 67.4% 87.2% 96.2% 98.5% 99.5% 99.8% 99.8% 100.0% -Only 64% of isolates were inhibited by 1 mg/L of imipenem alone in the presence of ETX2514 (fixed at 4 mg/L) (red squares) susceptible to imipenem and meropenem, respectively, which improved to MEM

46.5% and 42.8% in the presence of ETX2514 and to 98.7%. and 99.0% when MIC90 value is highlighted with a red box and MIC50 value is highlighted with a blue box. ETX2514 was tested at a fixed sulbactam and ETX2514 (each fixed at 4 mg/L) were added to the concentration of 4 mg/L. IPM and MEM were added to SUL-ETX2514 at a fixed concentration of 2 mg/L carbapenem. A total of 73.6% and 75.4% of the P. aeruginosa isolates tested The activity of imipenem-ETX2514 is stable over time, across regions and sources of infection were susceptible to imipenem and meropenem, respectively, which improved -Sulbactam-ETX2514 was highly active against A. baumannii -Carbapenem-ETX2514 combinations were less active against A. baumannii to 94.7% and 82.6% in the presence of ETX2514. Adding sulbactam (fixed at -Addition of either carbapenem (fixed at 2 mg/L) did not improve the MIC90 of Imipenem Imipenem-ETX2514 Meropenem Meropenem-ETX2514 4 mg/L) to these combinations did not improve the potency of the carbapenem- -98.4% of isolates were inhibited by 4 mg/L sulbactam-ETX2514 sulbactam-ETX2514 (red squares) but significantly improved the MIC50 (blue Year n Range MIC50 MIC90 Range MIC50 MIC90 Range MIC50 MIC90 Range MIC50 MIC90 ETX2514 combinations against P. aeruginosa. -Only 27% of isolates were inhibited by 4 mg/L sulbactam alone squares) 2013 202 0.12->32 1 16 ≤0.03->32 0.25 1 ≤0.03->32 0.5 16 ≤0.03->32 0.25 8 Conclusions 2014 196 0.12->32 1 16 ≤0.03->32 0.25 1 ≤0.03->32 0.5 16 ≤0.03->32 0.25 8 A triple combination of imipenem or meropenem plus sulbactam and ETX2514 The activity of sulbactam-ETX2514 is stable over time, across regions and sources of infection demonstrated potent antibacterial activity against recent, geographically 2015 204 0.12->32 1 16 ≤0.03->32 0.25 1 ≤0.03->32 0.5 16 ≤0.03->32 0.25 8 diverse clinical isolates of A. baumannii and P. aeruginosa. These data support SUL SUL-ETX2514 SUL-ETX2514-IPM SUL-ETX2514-MEM Region the continued development of ETX2514 in combination with sulbactam and/or Year n Range MIC MIC Range MIC MIC Range MIC MIC Range MIC MIC Asia-Pacific 103 0.25->32 1 16 ≤0.03->32 0.25 1 ≤0.03->32 0.5 16 ≤0.03->32 0.25 16 a carbapenem against A. baumannii and P. aeruginosa. 50 90 50 90 50 90 50 90 2013 201 0.5->32 16 >32 0.06-16 1 4 ≤0.03-16 0.25 2 ≤0.03-16 0.25 2 Europe 200 0.25->32 1 16 ≤0.03->32 0.25 1 ≤0.03->32 1 16 ≤0.03->32 0.5 8

Introduction 2014 205 0.5->32 16 >32 0.12->32 1 2 ≤0.03->32 0.12 1 ≤0.03->32 0.25 2 Latin America 106 0.5->32 1 16 ≤0.03->32 0.25 2 ≤0.03->32 1 32 ≤0.03->32 0.5 16 North America 193 0.12->32 1 8 ≤0.03-8 0.25 0.5 ≤0.03->32 0.5 8 ≤0.03->32 0.25 2 Sulbactam-ETX2514 is a 2015 202 0.5->32 16 >32 0.12-16 1 2 ≤0.03-8 ≤0.03 1 ≤0.03-16 0.12 1 Source of Infection β-lactam/β-lactamase inhibitor Region combination currently in clinical Blood 72 0.5->32 1 8 ≤0.03->32 0.25 1 0.06->32 0.5 4 ≤0.03->32 0.25 4 Asia-Pacific 107 0.5->32 32 >32 0.06-16 1 2 ≤0.03-16 0.5 2 ≤0.03-8 0.5 2 development for the treatment Respiratory 301 0.12->32 1 16 ≤0.03->32 0.25 1 ≤0.03->32 0.5 16 ≤0.03->32 0.25 8 of resistant A. baumannii Europe 196 0.5->32 32 >32 0.12->32 1 2 ≤0.03->32 0.25 2 ≤0.03->32 0.25 2 infections (Durand-Réville et al. Skin/Soft Tissue 143 0.12->32 1 16 ≤0.03->32 0.25 1 ≤0.03->32 0.5 16 ≤0.03->32 0.25 8 (2017) Nature Microbiol. in North America 194 0.5->32 4 >32 0.12-16 1 2 ≤0.03-8 ≤0.03 1 ≤0.03-16 0.25 1 Urinary Tract 34 0.5->32 1 8 0.06->32 0.25 1 0.06->32 0.5 16 ≤0.03->32 0.25 4 press) Latin America 111 0.5->32 16 >32 0.12-4 1 2 ≤0.03-4 ≤0.03 1 ≤0.03-4 0.5 1 Other 52 0.5->32 1 16 0.12->32 0.25 1 0.06->32 1 8 ≤0.03->32 0.5 4 ETX2514 is a novel BLI from a series of diazabicyclooctenones with best-in- Total 602 0.12->32 1 16 ≤0.03->32 0.25 1 ≤0.03->32 0.5 16 ≤0.03->32 0.25 8 class broad spectrum activity against Class A, C and D b-lactamases. Source of Infection Here we measure the antibacterial potency of a triple combination of Blood 106 0.5->32 16 >32 0.25-4 1 2 ≤0.03-4 0.25 2 ≤0.03-8 0.25 2 ETX2514 was tested at a fixed concentration of 4 mg/L. sulbactam, ETX2514, and imipenem or meropenem against recent and geographically diverse P. aeruginosa and A. baumannii isolates. Respiratory 301 0.5->32 16 >32 0.12-16 1 2 ≤0.03-16 0.25 1 ≤0.03-16 0.25 2 Conclusions Skin/Soft 122 0.5->32 16 >32 0.06->32 1 2 ≤0.03->32 ≤0.03 1 ≤0.03->32 0.25 2 Study Design Tissue • ETX2514 restores sulbactam antibacterial activity against a global collection of 608 A. baumannii clinical isolates with an MIC90 of 2 mg/L Methods: BLI Urinary Tract 33 1->32 8 >32 0.25-2 0.5 2 ≤0.03-1 ≤0.03 1 ≤0.03-4 ≤0.03 1 • Addition of 2 mg/L imipenem or meropenem does not change the MIC of sulbactam-ETX2514 versus A. baumannii Broth microdilution susceptibility testing was conducted at JMI Laboratories 90 according to CLSI guidelines using cation-adjusted Mueller-Hinton broth. Other 46 1->32 16 >32 0.12-8 1 2 ≤0.03-2 ≤0.03 2 ≤0.03-4 0.06 2 • ETX2514 restores imipenem antibacterial activity against a global collection of 602 contemporary P. aeruginosa clinical with an MIC90 of 1 mg/L Organisms: Total 608 0.5->32 16 >32 0.06->32 1 2 ≤0.03->32 0.12 2 ≤0.03->32 0.25 2 All isolates were collected from geographically diverse medical centers located in • These data support development of ETX2514 in combination with sulbactam for the treatment of A. baumannii and ETX2514 in United States, Europe, Latin American and the Asia-Pacific region as part of the ETX2514 was tested at a fixed concentration of 4 mg/L. IPM and MEM were added to SUL-ETX2514 at a fixed concentration of 2 mg/L. combination with imipenem against P. aeruginosa. SENTRY surveillance program during 2013, 2014 and 2015.

Presented at Microbe 2017, New Orleans, LA June 2017