NEW HAVEN, Conn.—Backed by funding from CARB-X, Melinta Therapeutics is seeking a prime compound candidate to begin Investigational New Drug (IND) testing to treat drug-resistant bacterial infections. Development will continue on the company’s investigational pyrrolocytosine compounds, which are a novel class of antibiotics targeting bacterial ribosomes in entirely new ways.
“Our structure-based design efforts to create and optimize the pyrrolocytosine class of antibiotics have shown exciting promise, with several compounds demonstrating comprehensive activity and preclinical effect across the full set of bacterial ‘superbugs,’” said Dr. Erin Duffy, chief scientific officer at Melinta. “We believe this new class of antibiotics could be transformational in the fight against these urgent threats. The support and resources available through CARB-X will provide important assistance as we move to advance one or more pyrrolocytosines into clinical development.”
Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) was established by the Biomedical Advanced Research and Development Authority (BARDA), a branch of the US Department of Health and Human Services, to protect the country from a variety of chemical, biological, radiological and nuclear threats, as well as from pandemic influenza and emerging infectious diseases.
BARDA has not generally invested in products in advance of the establishment of human data testing, but knew that the preclinical drug discovery pipeline was a crucial investment in finding new protections against biological threats. In collaboration with the Wellcome Trust, a global charitable foundation dedicated to improving health, BARDA funded CARB-X to help address the threat of antibiotic resistance that will complicate any public health emergency. CARB-X is now one of the world’s largest public-private partnerships focused on preclinical discovery and development of new antibacterial products to help address the threat of antibiotic resistance.
Under the terms of the recently announced funding, Melinta will receive an initial $2.3 million to isolate its best candidate to progress to IND testing with the FDA. Once the best option is chosen, which Melinta expects to do by the end of the year, CARB-X will invest more money to help the company prep for IND testing—funding a battery of tests regarding safety, efficacy and toxicology in rodents and a non-rodent species, and finally in-vitro and in-vivo testing. Successful IND testing will trigger another round of funding to support the first-in-human testing program, with the possibility of up to $6.2 million to support the development.
What makes the Melinta candidates exciting is their focus on novel ways to target the bacterial ribosome in response to the alarming emergence of bacteria that have developed resistance to all existing drug classes. Currently these pathogens cause mortality rates approaching 50 percent in some infection types, making “superbugs” the most serious hospital-treated bacterial threat. In addition, the causative pathogen is often unknown, creating the need for therapies that cover the full range of potential bacteria. Melinta’s pyrrolocytosines have demonstrated comprehensive activity across the full set of bacterial “superbugs.”
“We are very enthusiastic about our two top candidates. We have done a thorough job with our candidate compounds, ascertaining characterization and optimization activity, and we have very promising early safety results. But, of course, the proof is in the pudding,” asserts Duffy. “While we are very enthusiastic about our candidates progressing with CARB-X support, we are also being good stewards of the program and the company by also continuing to develop new products behind our existing candidates in the event of an unanticipated setback.”
The ribosome has been the focus of ongoing research into its structure and workings for decades, as a prime target for immunologists and drug discovery pipelines. Antibiotics have proven effective against disease by attacking bacteria, disrupting their ribosomes and thus preventing the bacteria’s ability to create proteins needed to survive and reproduce. However, bacteria have developed resistance to many antibiotics that have targeted the same ribosome sites via similar mechanisms. While an estimated 60 to 70 percent of antibiotics work through targeting ribosomes, Melinta is focused on finding novel approaches.
“We are exploring an entirely new class of antibiotics, using a novel target site that has not yet shown antibiotic resistance, and one that is not currently targeted by existing antibiotics,” said Duffy. “We are using what we know, and an iterative structure design game to zoom in on the canvas, identify adjacent sites, and engineer an entirely new class of treatments.”