The CDC developed a three-dimensional computer-generated image of a group of carbapenem-resistant Enterobacteriaceae (CRE) bacteria. Photo credit: CDC
With the CDC’s having named carbapenem-resistant Enterobacteriaceae (CRE) an urgent public health threat, the call is out for new drugs with improved pharmacological properties. Infections caused by Klebsiella and Escherichia coli have attracted the attention of drug developers like The Medicines Co., Allergan, and Achaogen. The goal is to develop medications that move beyond the high-toxicity and low-efficacy profiles of older drugs.
As a class of beta-lactams, carbapenems are broad-spectrum antibiotics most effective against gram-negative infections. Enterobacteriaceae, a family of gram-negative bacteria including E. coli, house enzymes that can break down carbapenems, rendering them useless. CRE infections are difficult to treat and can turn deadly. The patients most susceptible are those who are already seriously ill.
The Medicines Co.’s investigational Carbavance (meropenem/RPX7009) is being studied in TANGO 2, a Phase III clinical trial with a beta-lactamase inhibitor-based combination targeting patients with CRE infections. In contrast to some recently approved drugs in this space, it is conducting its trial with infected patients.
“When a drug is approved, clinicians need information from real patients in the real world,” says The Medicines Co.’s Michael Dudley, SVP and head, R&D and co-leader of the infectious disease global innovation group. “That’s hard to do in the drug-resistant space because patients are at high risk for mortality and other issues.”
Achaogen’s lead product, Plazomicin, is being studied in two Phase III trials for bacterial infections due to MDR enterobacteriaceae, including CRE. The once-daily 30-minute IV infusion allows for use after discharge if needed. Top-line data from the EPIC trial, targeting patients with complicated UTIs, is expected in Q1 2017.
“We set out to design a new aminoglycoside,” says Dr. Kenneth J. Hillan, CEO of Achaogen.
Recent changes in regulatory practices and government oversight have benefited developers. Carbavance went from the chemist’s benchtop to Phase III trials in as few as four years. According to Dudley, that’s a testament to his team, the FDA’s commitment to move programs forward, and the support of private and public partnerships.
Hillan commends the FDA and EMA for supporting drug developers in this space. “There’s a call for better alignment between the different regulatory authorities so drug developers don’t have to run two clinical-trial pathways,” he adds. “We need to streamline the regulatory process to increase the desire to invest in the space.”
Dr. David Nicholson, brand research and development head at Allergan, stresses continued R&D investment and public–private partnerships in developing new antibiotics. Allergan and AstraZeneca are studying ATM-AVI, a fixed-dose combo of aztreonam and avibactam, to treat a subtype of CRE. “It’s important for pharma to work with the government to advance efforts,” Nicholson says.