AKAO 2017 Annual Report

16 frequently ventilated and unconscious, planned assessments of hearing and tinnitus were not possible for many of the patients. In Cohort 2, study drug-related TEAEs related to renal function were reported in 13.3% of patients and no TEAEs related to cochlear or vestibular function were reported. Research and Development Programs Beyond our plazomicin program, the research and development teams are focused on discovering novel medicines for serious unmet medical needs. We have assembled a well-balanced portfolio of small molecule and antibody programs. Our small molecule programs focus on our core areas of expertise in gram-negative antibacterial discovery and development. Our antibody portfolio is a blend of infectious disease programs and non-infectious disease programs that are well suited for our innovative antibody discovery methods. We continue to attract key talent and leadership within our research and early development organization to enable efficient transition of molecules from discovery through Phase 1. In addition to our strong internal expertise, we have a long history of engaging world-class research and clinical experts across academia and industry to increase the likelihood of success of our research programs. We also maintain active collaborations with academic research groups to enable the rapid flow of cutting edge science into biotechnology translation. Additional detailed information regarding our C-Scape program is included below, as well as information regarding our research programs. C-Scape Development Program Between 10% and 30% of clinical Enterobacteriaceae isolates in the United States and EU produce ESBLs, rendering them resistant to all -lactam antibiotics except for carbapenems. The majority of these isolates are also resistant to all oral therapy options for serious infections, including fluoroquinolones, trimethoprim- sulfamethoxazole and cephalosporins. Consequently, the use of carbapenems is increasing rapidly; for instance, in 2009, 100,000 patients hospitalized for a cUTI in the United States received a carbapenem and in 2014 over 350,000 patients received a carbapenem. In the setting of cUTI, including AP, physicians are faced with a dilemma of treating a patient empirically with oral antibiotics in the outpatient setting, which risks treatment failure in a significant proportion of cases, or admitting the patient to the hospital for intravenous carbapenem therapy, which in many cases is an inappropriate use of a “last-line” antibiotic therapeutic option. A new oral antibiotic is needed to reduce the burden and cost of hospitalization, spare carbapenem use, reduce the complications associated with the use of IV catheters, and minimize the risk of oral antibiotic treatment failure. To address this unmet medical need, we are developing C-Scape, a fixed-dose oral combination of two FDA-approved agents: ceftibuten, a third- generation cephalosporin, and clavulanate, a -lactamase inhibitor, for the treatment of adult patients with cUTI caused by Enterobacteriaceae, including ESBL-producing and fluoroquinolone-resistant strains, where limited oral treatment options exist currently. C-Scape is potent against the target pathogens. In a panel of 387 ESBL-producing Enterobacteriaceae from hospitalized patients with UTIs in the U.S. and EU (2014-2015), C-Scape achieved an MIC90 of 1 — g/mL. Moreover, in vitro time-kill experiments have shown that C-Scape is rapidly bactericidal against ESBL-producing Enterobacteriaceae. Based on these data the FDA granted C-Scape a QIDP designation in January 2017. We believe that C-Scape has the potential to rapidly address a serious unmet need for an effective oral treatment for patients with cUTI, including AP, caused by ESBL-producing Enterobacteriaceae. Both ceftibuten and clavulanate have been previously approved by the FDA, therefore we expect C-Scape to qualify for the 505(b)(2) NDA regulatory pathway for the combination product, which would permit the application to rely in part on the FDA’s findings of safety and effectiveness for each compound alone, and FDA’s guidance for Antibacterial Therapies for Patients with Unmet Medical Need for the Treatment of Serious Bacterial Diseases. We conducted a Phase 1 multiple-dose pharmacokinetic study during the second half of 2017. The Phase 1 results are being evaluated in conjunction with existing human pharmacokinetic data and newly generated nonclinical pharmacokinetic/pharmacodynamic data to inform dose selection for a Phase 3 study. We intend to initiate a single pivotal Phase 3 study in patients with cUTI, including AP, who are suitable for treatment with oral antibiotics, in 2018. If successfully developed and approved, we anticipate C-Scape may be eligible for three years of new clinical investigation exclusivity under the Hatch Waxman Act, with an additional five years of non-patent exclusivity conferred by QIDP designation. C-Scape is funded, in part, with Federal funds from BARDA, Office of the Assistant Secretary for Preparedness and Response, Office of the Secretary, U.S. Department of Health and Human Services, under Contract No. HHSO100201700021C.