AKAO 2017 Annual Report

10 The comparator chosen for this study, meropenem, is a member of the carbapenem class of antibiotics. Due to their preserved activity against pathogens resistant to third generation cephalosporins (e.g., ESBL-producing organisms) and other antibiotic classes, carbapenems are considered the last line of defense against MDR gram-negative infections and are thus often reserved to treat such infections. In terms of safety, the overall incidence of treatment emergent adverse events, including serious adverse events, was similar across the plazomicin and meropenem groups. The demonstration of non-inferiority of plazomicin, including against key resistant pathogens, to an agent widely considered to be preferred therapy for MDR infections, combined with a generally favorable safety profile positions plazomicin as a potential alternative to carbapenems in this indication. • A lower rate of mortality or serious disease-related complications was observed for plazomicin compared with colistin therapy in the Phase 3 CARE trial in patients with serious infections due to CRE. Favorable safety profile of plazomicin compared to colistin in a critically ill patient population in CARE trial . In Cohort 1 of CARE, plazomicin-based therapy was associated with a lower rate of 28- day all-cause mortality or serious disease related complications as well as lower 28-day all-cause mortality alone compared to colistin-based therapy in the treatment of CRE BSI and hospital acquired and ventilator associated bacterial pneumonia. By focusing the Phase 3 CARE trial on patients with a high unmet medical need where the efficacy of the currently available therapy is often inadequate, we observed improved outcomes for plazomicin compared with colistin therapy against CRE in the clinical setting. Plazomicin based therapy was also associated with an improved safety profile compared to colistin, including a notable reduction in adverse events related to renal function. The large reduction in mortality combined with improved safety outcomes compared to colistin, a currently available agent for CRE infection, positions plazomicin as a potential new therapeutic option for serious infections due to CRE. Inclusion of a second, single-arm observational cohort (Cohort 2) in the Phase 3 CARE trial that enrolled patients not eligible for the randomized portion of the trial, allowed us to generate additional important data regarding the efficacy and safety of plazomicin as well as the use of TDM in an expanded patient population. • Convenient administration as once daily, 30-minute IV therapy. Plazomicin is intended to be administered as an IV infusion once per day for 30-minutes whereas other approved gram-negative IV antibiotics, such as -lactam antibiotics, are administered multiple times per day with infusion times up to two hours. In particular, if approved, we believe the improved convenience of this administration would facilitate plazomicin for outpatient therapy. • Potential to reduce the healthcare costs associated with the treatment of serious infections . Treatment of antibiotic-susceptible infections is associated with lower overall costs as compared to the treatment of antibiotic-resistant infections. As demonstrated in our Phase 3 CARE trial, plazomicin was associated with a 33% absolute reduction in 28-day all-cause mortality in patients with BSI compared to colistin. Additionally, the survival benefit was sustained through day 60. These data will allow us to model the potential health economic value of plazomicin. • Potential to improve dosing strategy compared to existing aminoglycosides and alternative therapeutic options, and individualized patient dosing using an in vitro assay . We have taken advantage of recent innovations in PK and pharmacodynamic (“PD”) modeling to create a once-a-day dosing regimen that is optimized to achieve the drug exposures projected to be efficacious in treating serious CRE infections. Patient dosing in the Phase 3 CARE trial population was also individualized by using an in vitro drug-monitoring assay to measure levels of plazomicin in the bloodstream and adjusting the dose, if necessary, to achieve the targeted drug exposure in critically ill patients. • Potential to be used in combination therapy for the treatment of serious infections due to CRE . Combination therapy has become the standard of care for treatment of serious infections due to CRE. Aminoglycoside/ -lactam combinations may be particularly attractive based on in vitro evidence of synergistic bacterial killing and decades of experience in the use of such combinations for the treatment of difficult gram-negative pathogens. We believe in vitro data demonstrating synergistic bacterial killing against CRE with select plazomicin combinations in addition to the clinical data generated with the use of combination therapy in the Phase 3 CARE trial provides support to the use of plazomicin as part of active combination therapies for select patients.