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A second candidate against MDR infections
SOUTH SAN FRANCISCO, Calif.—Late-stage biopharma Achaogen Inc. rang in the new year by heralding positive top-line results from its Phase 1 clinical study of C-Scape, the company’s second antibacterial candidate being developed for multi-drug resistant (MDR) gram-negative infections. C-Scape, an oral drug, was found to be well tolerated across all doses studied in the Phase 1 trial, with no drug-drug interaction between the previously approved compounds when dosed in combination.
Achaogen believes the greatest unmet medical needs lie among infections due to MDR gram-negative bacteria, where the problem is extensive and growing and the industry pipeline of drug candidates is sparse.
“The positive top-line results from this first-in-human clinical trial for C-Scape are supportive of further evaluation, and we continue to plan for Phase 3 in 2018,” states Kenneth Hillan, president of Achaogen R&D. “The FDA has previously indicated that a single Phase 3 study in cUTI [complicated urinary tract infections], if successful, would be sufficient for licensure, and we plan to meet with the FDA in early 2018 to seek agreement on the details of our development plan.”
C-Scape has been awarded Qualified Infectious Disease Product (QIDP) status by FDA for the treatment of cUTI, including acute pyelonephritis. QIDP designation provides incentives for new antibiotic treatments, including priority review and additional market exclusivity.
“Given the need for additional oral antibiotic options for infections due to ESBL-producing Enterobacteriaceae, we plan to pursue a 505(b)(2) development pathway to take advantage of the development studies performed on ceftibuten and clavulanate, the two previously approved component drugs of C-Scape,” Hillan adds.
Achaogen CEO Blake Wise says, “ESBL-producing Enterobacteriaceae are generally resistant to currently available oral therapies. The lack of adequate oral therapies leads to patients needing to be hospitalized to receive intravenous therapy.”
“New oral agents with activity against ESBL-producing organisms are badly needed to reduce hospitalization and the reliance on IV carbapenems,” he continues. “We estimate that there are over 500,000 of these infections annually in the U.S., and this number continues to grow.”
There are an estimated three million cUTI patients treated in hospitals each year in the U.S., with more treated in the community, Wise says. Urinary tract infections are considered complicated when any functional or structural abnormality of the genitourinary tract is present, or when the infection has ascended to involve the kidneys (termed acute pyelonephritis).
“Based on what we learned in our recently completed Phase 1 trial, we remain focused on initiating the Phase 3 program this year,” Wise says. “Prior to that, we’ll be working towards developing a comprehensive package for a pre-Phase 3 meeting with the FDA, which will include clinical and non-clinical information about C-Scape.”
“We are currently evaluating the Phase 1 data in the context of our preclinical efficacy targets to inform dose selection for Phase 3,” he adds. “We plan to begin the Phase 3 trial in 2018 with the potential to then submit a New Drug Application to the FDA. If approved, we expect C-Scape to be used in the treatment setting for patients with MDR infections rather than as a preventative measure.”
Both the World Health Organization (WHO) and the U.S. Centers for Disease Control see MDR infections as a serious public health threat in hospitals around the world.
“This is an ever-growing problem in hospitals and a serious threat to certain patients,” Wise says. “Our ultimate goal is to improve patient health outcomes and reduce hospitalization by treating certain MDR infections in the outpatient and possibly oral step-down settings.”
Dr. Yoav Golan of Tufts Medical Center states, “There is a tremendous need for orally administered antibiotics with activity against MDR pathogens, such as ESBL-producing Enterobacteriaceae. For patients suffering from complicated urinary tract infections due to ESBL-producing Enterobacteriaceae, intravenous carbapenem therapy is often their only treatment option. I would welcome a new oral beta-lactam and beta-lactamase inhibitor combination that would help limit use of carbapenems in these patients.”
The WHO has declared antibiotic resistance a threat to global health security, stating that two million people a year in the United States alone become infected with antibiotic-resistant bacteria, with 23,000 people dying each year as a direct result of antibiotic-resistant infections. Furthermore, patients spend many additional days in the hospital as a result of resistant infections, costing $20 billion annually in the United States.
By 2050, antimicrobial resistance is projected to result in about 10 million deaths per year and a global loss in gross domestic product of more than $100 trillion, the organization estimates.
Achaogen’s Phase 1 clinical trial was a double-blind, randomized, placebo-controlled, parallel group study to assess the safety, tolerability and clinical pharmacology of C-Scape, administered orally, in 41 healthy subjects.
The combination of ceftibuten and clavulanate was well tolerated when administered for 14 days across all dosing regimens tested, and no serious adverse events, grade 3 or 4 adverse events or adverse events leading to discontinuation of study drug were observed. The safety profile was consistent with expectations for ceftibuten and clavulanate when administered based on existing product labels; also, preliminary pharmacokinetics following administration of ceftibuten and clavulanate in combination were similar to those following administration of each compound alone, indicating no drug-drug interaction between ceftibuten and clavulanate.