AKAO 2017 Annual Report

14 Completed Phase 1 and Phase 2 Clinical Studies Study No. Objectives Number Enrolled Key Result 001 Phase 1 trial of safety and PK after single and multiple doses in healthy subjects 39 Plazomicin was well tolerated at doses of up to 15 mg/kg for 3 days. 003 Phase 1 trial of safety, plasma PK and lung penetration in healthy subjects 40 Plazomicin was well tolerated at doses of up to 15 mg/kg for 5 days. Plazomicin penetrated into the lung to a similar degree as other aminoglycosides. 004 Phase 1 trial of safety and PK in healthy and impaired kidney function subjects 24 As with other aminoglycosides, plazomicin’s dose needs to be adjusted in patients with moderately or severely impaired kidney function. 006 Phase 1 thorough QT/QTc trial in healthy subjects 64 Plazomicin showed no clinically relevant potential to increase risk for cardiac arrhythmias at single doses of up to 20 mg/kg. 010 Phase 1 study to assess the metabolism, excretion, and mass balance of plazomicin in healthy subjects 6 97% of plazomicin dose recovered as parent drug in the urine, demonstrating metabolism of plazomicin (if any) is negligible 011 Phase 1 study to evaluate the drug-drug interaction potential between plazomicin and metformin in healthy subjects 16 Plazomicin is not an in vivo inhibitor of organic cation transporter 2 (OCT-w) or multidrug and toxin extrusion 2K (MATE-2K) 002 Phase 2 safety, efficacy, and PK in patients with cUTI 145 Plazomicin displayed efficacy similar to the comparator antibiotic treatment (levofloxacin). Plazomicin was generally well tolerated at doses of up to 15 mg/kg for 5 days. Phase 3 EPIC Trial of Plazomicin for the Treatment of cUTI Our Phase 3 EPIC trial was a randomized, multicenter, multinational, double-blind study of the efficacy and safety of plazomicin compared with meropenem in the treatment of cUTI, including AP, in adults, and allowed an optional switch to oral therapy. We compared plazomicin 15 mg/kg IV given once daily to meropenem 1.0 gram IV every eight hours with the option to switch to open-label levofloxacin after a minimum of four days of blinded IV study drug to complete a total of 7 to 10 days of therapy (IV plus oral). The trial was designed to show that plazomicin was non-inferior to meropenem based on the FDA primary endpoint of composite clinical and microbiological cure and the Day 5 and TOC visits and the EMA primary endpoint of microbiological eradication at the TOC visit in the mMITT and ME populations. We enrolled 609 patients in the EPIC trial. Plazomicin successfully met the objective of non-inferiority compared to meropenem for the FDA-specified primary efficacy endpoint, and achieved superiority for the EMA-specified primary efficacy endpoint. Results for the FDA pre- specified composite endpoint of clinical cure and microbiological eradication in the mMITT population were as follows: Day 5: 88.0% plazomicin vs. 91.4% meropenem (difference –3.4%, 95% confidence interval (“CI”): – 10.0% to 3.1%), indicating non-inferiority; and Test-of-Cure: 81.7% plazomicin vs. 70.1% meropenem (difference 11.6%, 95% CI: 2.7% to 20.3%), indicating statistically favorable outcomes for plazomicin compared to meropenem. Results for EMA-specified endpoints of microbiological eradication at the test-of-cure visit were as follows: mMITT: 87.4% plazomicin vs. 72.1% meropenem (difference 15.4%, 95% CI: 7.5% to 23.2%), indicating statistical superiority; microbiologically evaluable (“ME”): 90.5% plazomicin vs. 76.6% meropenem (difference 13.9%, 95% CI: 6.3% to 21.7%), indicating statistical superiority. Consistent with the overall results of the primary endpoint at the TOC visit, plazomicin showed comparable or higher cure rates to meropenem in the subgroups of patients with infection caused by ESBL-producing, aminoglycoside-resistant, and/or CRE. These results demonstrate the potential utility of plazomicin as treatment for cUTI, including AP, where treatment options are limited and help to position plazomicin as an alternative to carbapenems in the treatment of urinary tract infections due to ESBL-producing and other MDR gram-negative pathogens. Plazomicin was well tolerated with no new safety concerns identified in the EPIC trial. Total treatment emergent adverse events (“TEAEs”) related to renal function were reported in 3.6% and 1.3% of patients in the plazomicin and meropenem groups, respectively. TEAEs related to cochlear or vestibular function were reported in