The Medicines Co.'s intravenous antiplatelet agent cangrelor is taking center stage Wednesday because of an FDA advisory panel, but backers of the Parsippany, N.J.-based firm increasingly are looking at the rest of the pipeline, including the reformulated version of the intravenous Minocin (minocycline), RPX-602, due for a decision on approval from U.S. regulators this month.

Interest steadily mounts in new, non-antibiotic strategies against multidrug-resistant pathogens, noted Roth Capital Partners analyst Joseph Pantginis, citing among the early stage players Ampliphi Biosciences Corp., of Glen Allen, Va., which is using bacteriophage (shorthanded "phage") technology to come up with more effective approaches to ever-hardier bugs. The firm has a lead program in methicillin-resistant Staphylococcus aureus (MRSA), followed by one in Pseudomonas aeruginosa infections in cystic fibrosis and another in Clostridium difficile.

The lead program is in the works via collaboration with the U.S. Army. "We partnered with them about two years ago to develop a targeted solution for MRSA that they're finding throughout the world," Baxter Phillips, Ampliphi's chief business officer, told BioWorld Today. A phase I trial is expected to start around the end of this year. "What the Army is finding is that, particularly in the Middle East, where antibiotics are given out without thought or proper consideration of what the end treatment goal is, there are highly resistant and multiply resistant species in that region," he said.

The undisciplined use of antibiotics has "really exacerbated this onslaught of multidrug-resistant bacteria," in general, Phillips said. "We see it in any region where there is perhaps a more liberal use of antibiotics. For example, in southern Europe, we know that there are significantly higher rates of multidrug-resistant species occurring in Italy, Portugal and Greece, where they use antibiotics quite freely. In northern Europe, where they're relatively well conserved and used only in instances where [doctors] are certain there's a bacterial infection, incidence and rates are quite low" of multidrug resistance.

Described as the world's most abundant organisms, phages number more than ten thousand billion billion billion on earth, and prey only on bacteria, never on human cells or those of any more complex organism. While resistance mechanisms do exist, as living organisms phages are constantly changing and adapting alongside their host bacteria, bypassing the development of resistance, and making them ideal for antibiotic development, as researchers discovered in the early 1900s.

"As the evolution of small-molecule antibiotics came about, the Western world, favoring the small-molecule approach, steered toward penicillin, tetracycline, etc.," Phillips said. "Phage, for some reason, was swept up into Eastern Europe, Russia, the Soviet Union. It was effectively well hidden for decades. Lately, in the mid-2000s or so, it was noted that there's never been proper characterization" of phages, or precise matching of phages to their targets, he said. Ampliphi believes it has surmounted that hurdle as well as another: manufacturing. The firm recently established a new and first-in-class GMP-ready phage production facility in Ljubljana, Slovenia – "likely the first of its kind," noted Roth's Pantginis.

"With regard to the regulatory pathway," Phillips said, "it's probably still being ironed out. It doesn't quite 100 percent fit the mold of the standard small-molecule pathway. At the same time, it doesn't quite 100 percent fit the mold of your standard annual vaccination. It's a bit of a blend. We're effectively introducing a live virus" – in some cases, as with Pseudomonas, in quite high concentrations. "It's important, certainly, to understand the effects that the inhalation of this type of viral load may have on the lungs," he said. "We believe phage is very safe. We're not aware of any known reports of any qualified phage products causing any type of significant reaction. The FDA, European Medicines Agency and other regulatory parties will certainly hold us to the same high standards of small-molecule development, with the potential added complexity that phage, once it's entered [the body], doesn't have the standard pharmacokinetic/pharmacodynamic profile of a standard small molecule. Phages actually work by infecting the host, i.e. the bacteria, and replicating, and when they replicate they create hundreds of phages that go out and spread and continue to infect the target bacteria until the infection is eradicated."

FUNDED INTO MID-2016

Behind MRSA, Ampliphi is "rapidly moving forward to advance our Pseudomonas products," and has identified potential infection-killing candidates by way of tests with samples taken from Europe, the U.S., and Australia, Phillips said. "We're characterizing a few more phages to see if we can optimize our final product mix." Nebulizer qualification studies are slated for the third quarter of this year. The C. difficile program comes next in line.

"Fortunately, the tide is somewhat turning for companies' interest in antibacterial research and development," Phillips said. "Roche has done a novel job, somewhat leading the pathway, having abandoned antibacterial R&D back in the early 2000s, and now coming back full force re-entering with quite some vigor in their partnering." An example is Basel, Switzerland-based Roche AG's deal worth up to CHF465 million (US$510.6 million) in up-front and milestone payments with Polyphor Ltd., of Allschwill, Switzerland. The agreement is based on the antibiotic program POL7080 for treating P. aeruginosa infections. (See BioWorld Today, Nov. 5, 2013.)

"We like to look at ourselves as the world's leading player in bacteriophage," Phillips said, adding that the firm is constantly in search of "other parties, small companies or universities, that may have complementary programs to our own."

The report by Roth's Pantginis also mentions Contrafect Corp., of Yonkers, N.Y., which went public last summer to advance its early stage pipeline against drug-resistant pathogens, including a lead lysine candidate for S. aureus bacteremia and an antibody combo candidate for influenza. Phillips described Contrafect as "on the outskirts" of the field, since the firm's interest lies not in using the whole phage but an enzyme that naturally occurs on its surface and can break down some bacterial cell walls. (See BioWorld Today, July 30, 2014.)

Another contender is Nanjing, China-based Phagelux Inc., which in January made a deal with Delaware-registered Iveria Technologies Inc. to acquire several biodegradable polymer delivery systems for its phage technologies being developed for human and agricultural uses. Phillips said the firm seems "more interested in the food-health application, rather than a human therapeutic." (See BioWorld Today, Jan. 7, 2015.)

More therapeutic-based is Lisbon, Portugal's Technophage SA, which last July received authorization of its investigational new drug application for TP-102, described as "a bacteriophage cocktail" for the treatment of infected chronic ulcers, namely diabetic foot infections.

"There are oftentimes many different isolates beneath the primary species" targeted by the phage. Killing those primarily prevalent isolates "may take two or three phages in order to guarantee you can properly cover the most prevalent isolates," but each phage is viewed by regulators as a separate product, all of them combined in a single drug, Phillips said. Three to five phages is "cumbersome, but fairly manageable" from an approval and manufacturing standpoint, he said.

"A few weeks ago we closed on a $13 million round of financing, with current and new institutional investors," Phillips said, adding that the funds on hand should last well into mid-2016. "By that time, we expect to have multiple clinical signals, which we believe will help support and validate the company and either generate additional interest from investors or help solidify the current interest we have from big pharma and potential partners," he said.