AKAO 2017 Annual Report

4 product may be awarded upon approval. We have global commercialization rights to plazomicin, which has patent protection in the United States estimated from 2030 to 2032. Plazomicin has been evaluated in two Phase 3 clinical trials, entitled EPIC and CARE. The EPIC study was a Phase 3 trial of plazomicin for the treatment of patients with cUTI and AP and enrolled 609 patients. In the EPIC trial, plazomicin successfully met the objective of non-inferiority compared to meropenem for the FDA-specified primary efficacy endpoints, and achieved superiority for the primary efficacy endpoints specified by the European Medicines Agency (“EMA”). Results for the FDA pre-specified composite endpoint of clinical cure and microbiological eradication in the microbiological modified intent-to-treat (“mMITT”) population at Day 5 achieved statistical non-inferiority, and outcomes at the Test-of-Cure (Day ~17) statistically favored plazomicin. Results for EMA-specified endpoints of microbiological eradication at the test-of-cure visit achieved statistical superiority in both the mMITT and microbiologically evaluable (“ME”) populations. Plazomicin was also generally well tolerated with no new safety concerns identified in the EPIC trial. The CARE study was a Phase 3 resistant pathogen trial designed to evaluate the efficacy and safety of plazomicin in patients with serious bacterial infections due to CRE. The CARE trial enrolled 69 patients, comprised of 39 patients enrolled in Cohort 1, comparing plazomicin to colistin-based therapy in patients with BSI infections or pneumonia due to CRE, and 30 patients in Cohort 2, a single arm cohort of plazomicin treatment in patients with serious infections due to CRE who were not eligible for Cohort 1. In Cohort 1 of the CARE trial, a lower rate of mortality at Day 28 or serious disease-related complications was observed for plazomicin compared with colistin therapy. The safety profile of plazomicin was favorable to that of colistin in critically ill patients in the CARE trial. According to government agencies and physician groups, including the CDC, the Infectious Disease Society of America, and the WHO, one of the greatest needs for new antibiotics is to treat MDR Enterobacteriaceae, including ESBL producing isolates and CRE. CRE leads to mortality rates of up to 50% in patients with BSI. We estimate that there were approximately 180,000 cases of CRE infections in the United States and five major markets in the EU in 2016 including France, Germany, Italy, Spain and the United Kingdom, which we refer to as the EU 5. Based on the significant increase in resistance rates in recent years, we anticipate CRE will continue to spread and remain a major health problem. Governments, in collaboration with the private sector, have begun to respond by advancing regulatory reform and economic incentives to spur development of new antibiotics. Plazomicin is a novel intravenous aminoglycoside antibiotic. Aminoglycosides have been used successfully for the treatment of serious infections for more than 50 years. However, clinical resistance to currently marketed aminoglycosides has increasingly limited their utility. We developed plazomicin by chemically modifying sisomicin, a naturally occurring aminoglycoside, in order to overcome common aminoglycoside resistance mechanisms. In MDR Enterobacteriaceae, including ESBL-producing isolates and CRE, plazomicin remains active where most other antibiotics, including commercially available aminoglycosides, have limited potency due to resistance. We consider the following to be key attributes that support the clinical utility and commercial value of plazomicin: • Potent in vitro and in vivo activity in nonclinical studies against MDR Enterobacteriaceae, including ESBL-producers and CRE. • Activity in the presence of a range of resistance mechanisms, including most aminoglycoside modifying enzymes, fluoroquinolone target site mutations, extended-spectrum -lactamases, and carbapenemases. • Demonstrated non-inferior (day 5) and statistically favorable (day 17) outcomes compared to meropenem in patients with cUTI/AP infections due to Enterobacteriaceae, including fluoroquinolone- resistant and ESBL-producing isolates, based on results from our Phase 3 EPIC study. • Lower rate of mortality and improved safety compared to colistin observed in patients with serious bacterial infections due to CRE, based on results from our Phase 3 CARE study. • Potential to improve dosing strategy, which includes individualized patient dosing using therapeutic drug management (“TDM”), an in vitro drug-monitoring assay, to potentially optimize both the efficacy and safety of plazomicin by dosing to a target drug exposure.