The bulk of the work in antibiotics is being done by small biotech companies, according to IDSA.
At newly formed Enbiotix, J. Ruben Morones-Ramirez, Ph.D., professor at Universidad Autónoma de Nuevo León, James J. Collins, Ph.D., and other scientists are showing that the addition of silver to standard antibiotics targeting gram-negative bacteria improves their efficacy between 100- and 1,000-fold.
“This is the first work to biochemically and genetically decipher the mechanisms by which silver treatment led to cell death,” said Dr. Morones-Ramirez.
Lab work shows that this approach enhances existing antibiotics, broadens the spectrum of vancomycin, and helps resensitize resistant bacterial strains.
“We’ve been approached by some pharmaceutical companies, such as Cubist Pharmaceuticals and Pfizer, that are interested in our work. We believe the technology of adding silver to antibiotic therapies will be explored much further and has a very nice shot at being successfully implemented as a therapeutic in approximately five years,” continued Dr. Morones-Ramirez.
The next stage of the company’s work will be to explore silver toxicity in higher organisms (that is, sheep) to move quickly into human trials.
Dr. Morones-Ramirez’s university laboratory is exploring nanotechnology as well as synthetic and systems biology to develop intelligent delivery systems and to design therapeutics that decrease toxicity and possible side effects from the antibiotics, silver, and their combinations to enable faster commercialization.
“We look for these therapeutics to be target-specific, have a controlled release, and stay in the body until the infection is gone,” explained Dr. Morones-Ramirez
Cubist Pharmaceuticals, since its founding in 1992, has focused on the acute care hospital environment and maintained a strong interest in antibiotics. “Antibacterials will be an important part of our future,” said Bonney.
“Gram-negative bacteria account for 80% more days of therapy than the methicillin-resistant Staphylococcus aureus (MRSA) market, so this is an area of real, unmet medical need and one that we are focused on at Cubist. Two of our Phase III antibiotics have been declared as Qualified Infectious Disease Products, gaining an extension of Hatch–Waxman exclusivity.”
Currently ceftolozane/tazobactam (CXA-201) is undergoing Phase III trials for cUTIs and cIAIs. Cubist also is planning a Phase III program for ceftolozane/tazobactam in hospital-acquired/ventilator-associated bacterial pneumonia. That drug targets gram-negative bacteria.
“Pseudomonas aeruginosa is high on that [gram-negative target] list,” according to Bonney. The FDA granted fast-track status for all three indications.
Surotomycin (CB-315), an oral lipopeptide, is in Phase III for Clostridium difficile-associated diarrhea. “C. difficile is the number-one bacterial threat in the United States. Globally, it accounts for approximately 30 million days of treatment per year,” he continued, adding that Cubist expects to file an NDA in 2015.
In July, Tetraphase was granted the Qualified Infectious Disease Product (QIDP) designation for eravacycline (TP-434) in cIAIs and cUTIs. This designation enables priority review and eligibility for fast-track status, as well as the potential for a five-year extension of patent exclusivity.
The antibiotic is in Phase III trials for cUTIs. This synthetic, intravenously administered tetracycline is a broad-spectrum antibiotic for multi-drug-resistant infections. Additional compounds are in preclinical development. The company also is working to create oral antibiotics.
Achaogen is focused on multi-drug-resistant, gram-negative bacterial infections. In April, it was awarded a $60 million contract from the Biomedical Advanced Research and Development Authority (BARDA). The funds will be used to conduct a global Phase III study to evaluate the safety and efficacy of plazomicin for patients with gram-negative bacterial infections caused by carbapenem-resistant Enterobacteriaceae (CRE). The study is scheduled to begin during the fourth quarter of 2013. Plazomicin (ACHN-490) is a next-generation neoglycoside that has demonstrated efficacy against many pathogens.
AstraZeneca’s ceftaroline/avibactam (CAZ104) is in Phase II studies for cUTIs and cIAIs, and early results indicate potency against MRSA and enterobacteriaceae in vitro. This β-lactamase inhibitor, combined with cephalosporin, is expected to launch in the European Union and Japan the second half of 2014 and in China in 2016.
Zinforo, an extended-spectrum ceftaroline for pneumonia and skin infections, already has launched in Europe and is expected to launch in China in the first half of 2014.