Next up for Achaogen Inc. is a new drug application (NDA) filing with the FDA, expected in the second half of 2017, after the phase III EPIC (Evaluating plazomicin in cUTI) registration trial of lead candidate, plazomicin, met the agency's objective of non-inferiority compared to meropenem in patients with complicated urinary tract infections (cUTI) and acute pyelonephritis (AP). The trial also showed superiority in the EMA's primary efficacy endpoints of microbiological eradication at the test-of-cure (TOC) visit in both the microbiological modified intent-to-treat (mMITT) population and in the microbiologically evaluable (ME) population, with a marketing authorization application (MAA) filing in the EU expected in 2018.

The news sent Achaogen's shares (NASDAQ:AKAO) into overdrive Monday, accelerating throughout the day to a one-year high of $13.50 before closing at $13.03 for a gain of $7.78, or 148.2 percent. Volume of approximately 53 million shares was 168 times the stock's three-month moving average.

The South San Francisco-based firm wasted no time harnessing the momentum of its phase III success. Following Monday's market close, Achaogen filed for an underwritten public offering of up to 5.75 million common shares and granted underwriters a 30-day option to purchase up to 862,500 additional shares to fill overallotments. The offering was not priced, but based on Monday's close, the move could generate proceeds of $75 million, with another $11.2 million in the wings if the overallotment option is fully subscribed. As of Sept. 30, Achaogen reported $61.1 million in cash and equivalents.

Leerink Partners LLC, Stifel and Guggenheim Securities LLC are joint book-running managers for the offering, with Suntrust Robinson Humphrey Inc. as lead manager.

Plazomicin is an aminoglycoside designed to overcome most clinically relevant aminoglycoside resistance mechanisms, enabling the treatment of serious bacterial infections due to multidrug-resistant Enterobacteriaceae, including carbapenem-resistant Enterobacteriaceae, or CRE. The wholly owned program was developed by chemically modifying an existing aminoglycoside, sisomicin, to overcome common aminoglycoside resistance mechanisms.

In the EPIC trial, the composite endpoint at day five – both microbiological eradication and clinical cure rate in the mMITT population, according to Cortellis Clinical Trials Intelligence (CTI) – was 88 percent for plazomicin vs. 91.4 percent for meropenem, a difference of -3.4 percent (95 percent confidence interval [CI]: -10.0, 3.1 percent), indicating statistical non-inferiority. The composite endpoint at TOC – microbiological eradication and clinical cure rate in the ME population, according to Cortellis CTI – was 81.7 percent for plazomicin compared to 70.1 percent for meropenem, a difference of 11.6 percent (95 percent CI: 2.7, 20.3 percent), indicating statistical superiority.

For the EMA-specified endpoints, plazomicin showed microbiological eradication of 87.4 percent in the mMitt population at the TOC visit compared to 72.1 percent for meropenem, a difference of 15.4 percent (95 percent CI: 7.5, 23.2 percent), and microbiological eradication of 90.5 percent in the ME population at the TOC visit compared to 76.6 percent for meropenem, a difference of 13.9 percent (95 percent CI: 6.3, 21.7 percent. Both findings indicated statistical superiority for the study drug.

The multinational, randomized, controlled, double-blind EPIC trial enrolled 609 adults with cUTI and AP who were randomized 1:1 to plazomicin 15 mg/kg as a once daily 30-minute intravenous (I.V.) infusion or meropenem 1 gm every 8 hours as a 30 minute I.V. infusion. After a minimum of four days of I.V. therapy, patients who met protocol-defined criteria for improvement were allowed to step down to oral levofloxacin to complete seven to 10 days of I.V. plus oral therapy.

The mMITT population was defined as patients who received any amount of study drug and had a study-qualifying baseline urine culture. Only patients with qualifying baseline pathogen(s) susceptible to both study drugs were included. The ME population was defined as patients who qualified for the mMITT population, complied with key aspects of the protocol and had interpretable urine culture results at the day five and/or TOC visit.

Achaogen said plazomicin was well tolerated in the EPIC trial, with no new safety concerns identified. Treatment-emergent adverse events (TEAEs) related to renal function were reported in 3.6 percent and 1.3 percent of patients in the plazomicin and meropenem groups, respectively. TEAEs related to cochlear or vestibular function were reported in a single patient in each of the plazomicin and meropenem treatment groups. Both events were considered mild and resolved completely.

LIMITED USE INDICATION COULD BE IN THE OFFING

In addition to EPIC, Achaogen reported findings Monday from its phase III CARE (Combating Antibiotic Resistant Enterobacteriaceae) trial evaluating plazomicin in patients with serious infections due to CRE. In the descriptive trial, at day 28 all-cause mortality or significant disease-related complications – the combined primary endpoint – were 23.5 percent for plazomicin vs. 50 percent for those who received colistin, a difference of 26.5 percent (90 percent CI: -0.7, 51.2 percent). Day 28 all-cause mortality was 11.8 percent for plazomicin vs. 40 percent for colistin, a difference of 28.2 percent (90 percent CI: 0.7, 52.5 percent).

Colistin is one of the few remaining antibiotics to treat infections due to CRE.

The multinational, open label CARE trial included two cohorts of patients. Cohort 1 (N=39) was a randomized, comparator-controlled cohort to compare plazomicin with colistin (in combination with meropenem or tigecycline) to treat bloodstream infection (BSI), hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP) due to CRE. Cohort 1 enrolled 30 patients with BSI and nine patients with HABP/VABP. Cohort 2 (N=30) was a single-arm expanded access cohort to evaluate plazomicin-based therapy in patients with BSI, HABP/VABP or cUTI due to CRE who were not eligible for enrollment in Cohort 1. The primary analysis for Cohort 1 was conducted in the mMITT population of patients with confirmed CRE infection.

Achaogen said study drug-related TEAEs related to renal function were reported in 16.7 percent and 38.1 percent of patients in the plazomicin and colistin groups, respectively. No TEAEs related to cochlear or vestibular function were reported in either group.

Due to the small sample size, the company did not perform formal statistical hypothesis testing on the CARE trial. Nevertheless, Achaogen said it will include the CARE data along with the pivotal EPIC findings in its NDA and MAA filings.

On a conference call with analysts early Monday company officials maintained that Achaogen's favorable efficacy and safety profile supported a high probability of approval by both the FDA and EMA in cUTI and AP. The company expects to meet with regulators to discuss how the data, especially from CARE, also might enable a limited use indication in addition to the cUTI/AP indication.

The 21st Century Cures Act, passed last week, created a new limited population pathway for antibacterial drugs, or LPAD, intended to treat serious or life-threatening infections that occur in a limited population of patients with unmet medical needs. The provision is designed to provide the FDA with greater flexibility to approve antibiotics on the basis of a favorable benefit risk profile in the intended limited population, taking into account the severity, rarity or prevalence of the infection the drug is intended to treat and the availability or lack of alternative treatments. (See BioWorld Today, Dec. 2, 2016, and Dec. 8, 2016.)

The infections and patient population treated in CARE clearly fell within the category of infections to which the LPAD pathway was intended to apply, according to Achaogen.

Proceeds from the financing are designed to fund preparation and submission of regulatory filings, support the review process and enable the company to begin to prepare for a potential launch in the U.S. Achaogen already is working on clinical and non-clinical modules and associated manufacturing activities, and CMC work is underway.

Ex-U.S., the company plans to engage with potential partners, although officials did not outline a specific commercialization strategy.

The five-year consensus sales forecast for plazomicin is $161.3 million, according to Cortellis Competitive Intelligence.

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