AKAO 2017 Annual Report

15 a single patient in each of the plazomicin and meropenem treatment groups. Both events were considered mild and resolved completely. The first patient in our global Phase 3 EPIC trial for the treatment of cUTI and AP was enrolled in January 2016 and enrollment was closed in August 2016 with 609 patients. Top-line results were announced December 2016 and the FDA accepted the NDA for substantive review with a PDUFA target action date of June 25, 2018. We expect a commercial launch of plazomicin in the United States in 2018 if our NDA is approved by the PDUFA date. We also intend to submit an application for marketing authorization in the EU in 2018. Phase 3 CARE Trial of Plazomicin for the Treatment of CRE Our Phase 3 CARE ( C ombating A ntibiotic R esistant E nterobacteriaceae) trial was a resistant pathogen- specific trial designed to evaluate the efficacy and safety of plazomicin in patients with serious bacterial infections due to CRE. The study consisted of two cohorts of patients: • Cohort 1 – a randomized, comparator-controlled cohort to compare plazomicin 15 mg/kg IV once daily with colistin 300 mg loading dose followed by 5 mg/kg divided every eight hours or every twelve hours (each in combination with adjunctive meropenem or tigecycline) for the treatment of blood stream infections (“BSI”), or Hospital-Acquired Bacterial Pneumonia (“HABP”)/Ventilator-Associated Bacterial Pneumonia (“VABP”) • Cohort 2 – a single-arm observational cohort to evaluate plazomicin 15 mg/kg IV once daily in combination with adjunctive antibiotic therapy (investigator’s choice) in patients with BSI or HABP/VABP (who are not eligible for enrollment in Cohort 1); and to evaluate plazomicin monotherapy, followed by optional oral step-down therapy, in patients with cUTI, including AP The purpose of Cohort 2 was to allow access to plazomicin therapy for patients who were not eligible for enrollment in Cohort 1 and who had limited alternative treatment options available. This cohort includes two relatively distinct patient populations: 1) patients with colistin-resistant CRE or polymicrobial infections involving additional Gram-negative pathogens and thus higher anticipated mortality than patients enrolled in Cohort 1, and 2) those with low Acute Physiology and Chronic Health Evaluation (APACHE II) scores (< 15) and relatively less severe infection types (e.g. cUTI and AP) and thus lower anticipated overall mortality than patients enrolled in Cohort 1. Dosing of plazomicin in our Phase 3 CARE trial was individualized for each patient based on TDM. The use of TDM for currently marketed aminoglycosides has been shown to help achieve target drug exposures, leading to improved patient outcomes and reduced length of hospital stays. To support TDM, plazomicin plasma concentrations were determined using an investigational in vitro assay. In November 2013, we received an Investigational Device Exemption approval from the FDA for use of the assay in the trial. We closed enrollment in the CARE study in August 2016 with 69 patients; 39 patients with BSI or HABP/VABP due to CRE were randomized to Cohort 1 and 30 patients with BSI, HABP/VABP or cUTI due to CRE were enrolled in Cohort 2. In Cohort 1 of the CARE trial, a lower rate of mortality or serious disease-related complications was observed for plazomicin compared with colistin therapy. Results from Cohort 1 of the CARE trial were as follows: Day 28 all-cause mortality or significant disease related complications (primary endpoint): 23.5% plazomicin vs. 50.0% colistin (difference 26.5%, 90% CI: –0.7% to 51.2%); Day 28 all-cause mortality: 11.8% plazomicin vs. 40.0% colistin (difference 28.2%, 90% CI: 0.7% to 52.5%). Results from Cohort 2 of the CARE trial were as follows: Day 28 all-cause mortality or significant disease related complications: 39.1%; Day 28 all-cause mortality: 26.1%. The majority of deaths occurred in patients with additional Gram-negative pathogens ( Acinetobacter or Pseudomonas ), a condition excluded from Cohort 1. Two of four cUTI patients in Cohort 2 had clinical and microbiological cure at the TOC visit. The safety profile of plazomicin was favorable compared to that of colistin in the acutely ill patient population enrolled in the CARE trial. Study drug-related TEAEs related to renal function were reported in 16.7% and 38.1% of patients in the plazomicin and colistin groups of Cohort 1, respectively. No TEAEs related to cochlear or vestibular function were reported in either group. However, due to the clinical status of patients enrolled in the trial who were