Antibiotics development underwent “a bad period, and probably the low point was around 2009,” Melinta Therapeutics Inc. Chief Scientific Officer Erin Duffy told BioWorld Today. “But we’re really coming out of that, I think. You see it with the approvals in skin [infections], which was the only viable path there was for a while. Now you’re seeing it with us and other companies that hung in there” during a period of FDA scrutiny as well as public outcry.
But the slowdown had other reasons, too. “Our former CEO used to say, ‘Antibiotics are the cheapest life-saving drugs,’ because they are,” Duffy noted.
“You take them for 10 or 14 days and they cure you. That should be a wonderful thing, but if you’re the bean counter at a big company, and you’re looking at a lifestyle drug, or a cardiovascular drug, or a neuroscience drug, which you’re going to take chronically, or you’re looking at what you could possibly charge for an antibiotic, those numbers just don’t add up. What you’re seeing now,” she said, “is a continued improvement in terms of [the FDA] putting out guidance for different indications on how to do these studies. Are we all the way there yet? No, but boy are we making good progress.”
In the superbug world, Duffy said four areas hold promise. “Having multiple plays is the right place to go,” she said, with antibiotics in pursuit of the fastest-moving target in the pharmaceutical world. One area of research involves known classes that have been modified. Another is the beta lactamase inhibitors and their combinations. “None of these is a magic bullet, but a lot of them are going to be important new drugs,” she said.
Another space is that occupied by the likes of London-based Glaxosmithkline plc’s gyrase inhibitors and Melinta’s ESKAPE program, named with an acronym formed by the pathogens in its crosshairs: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, and Escherichia coli. Melinta has designed three new classes of antibiotics that show potent activity in the laboratory and in animal infection models. In the lead class, known as the pyrrolocytosines, several compounds shown comprehensive activity across the full set of bacterial superbugs, and New Haven, Conn.-based Melinta said candidates will enter the clinic in 2017.
In May, Melinta disclosed top-line results from the second phase III study with Baxdela (delafloxacin), an anionic quinolone in development for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI). Baxdela met the primary endpoints required by the FDA and EMA in the confirmatory pivotal experiment. With broad-spectrum activity against gram-positive and gram-negative bacteria, including methicillin-resistant S. aureus, Baxdela was tested as an intravenous (I.V.)-to-oral monotherapy against the standard of care, I.V.-only combination of vancomycin plus aztreonam.
LEG UP WITH 'GAME CHANGER’
Lifesci Capital analyst David Sherman, in a June 17 research report about a competing firm, pointed out that Baxdela’s “drug class, which includes many commonly used, approved antibiotics such as levofloxacin, moxifloxacin and ciprofloxacin, is associated with increased rates of tendonitis, tendon rupture, QT interval prolongation, and irreversible peripheral neuropathies. In October, the FDA’s Antimicrobial Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee met jointly to consider the use of fluoroquinolones and the labels’ warnings of serious adverse events. The negative view on fluoroquinolones suggests that Baxdela is not going to fully address the need in the community setting for a safe and effective oral antibiotic capable of treating resistant infections.”
Melinta, though, is optimistic. The firm used Captisol technology from Ligand Pharmaceuticals Inc., of San Diego, in formulating Baxdela for ABSSSI. Captisol is a chemically modified cyclodextrin, pioneered at the University of Kansas and designed to optimize the solubility and stability of drugs. It has enabled six FDA-approved products, including the likes of Thousand Oaks, Calif.-based Amgen Inc.’s Kyprolis (carfilzomib) for multiple myeloma, Deerfield, Ill.-based Baxter International Corp.’s Nexterone (amiodarone) for ventricular fibrillation and hemodynamically unstable ventricular tachycardia, and Kenilworth, N.J.-based Merck & Co. Inc.’s antifungal Noxafil (posaconazole). More than 30 Captisol-enabled products are moving through pipelines. (See BioWorld Today, May 13, 2016.)
One of the few antibiotics-focused small companies not snatched up by a larger concern, Melinta has been “very well supported by our investors over the years,” Duffy said. “We’re certainly open to partnerships of different varieties” and previously had a research collaboration with Paris-based Sanofi SA that was “very helpful.” But the company maintains independent strength. “We’re the antibiotics company,” she said. “That’s what our tagline is and that’s what we’d like to be. In the best of all scenarios, we would be the next Cubist, before they were acquired.” In late 2014, Kenilworth, N.J.-based Merck & Co. Inc. bought Cubist Pharmaceuticals Inc., of Lexington, Mass., in a deal equity-valued at $8.4 billion, and included $1.1 billion in net debt. (See BioWorld Today, Dec. 9, 2014.)
“Our ESKAPE program, we think, will be a game changer,” Duffy said. “That’s not to say resistance won’t evolve to a new class, but if you pick your mechanism well and you pick your chemistry well, cross-resistance to current therapies is not going to be there, so you’re starting with a leg up. You’re not starting in a place where there is already known resistance and [asking whether] it will, then, under selective pressure, rear its ugly face for you.”