Curing infections with poop in a pill
Two years ago, Catherine Duff, then 57, tearfully described eight debilitating bouts of antibiotic-resistant Clostridium difficile infection to a government panel in Washington. She grew better, she said, only after treating the gastrointestinal infection at home with her husband’s feces, a blender and an enema bag.
Mark B. Smith, a young doctoral student in microbiology, was in the audience, almost as teary as Duff. Resolving to help patients like her, he started a nonprofit called OpenBiome, the first stool bank in the country, which distributes fecal samples from healthy donors to help cure people with tenacious C. difficile infections.
Now OpenBiome has made the process, called fecal microbiota transplantation, far simpler. The bank has come up with a capsule containing fecal microbes that can be taken much like any other drug — poop in a pill.
“It’s such an obvious improvement,” Smith said.
C. difficile resides among trillions of other bacteria in normal, healthy humans. When antibiotics wipe out the competition, the bacteria spread through the gut, producing toxins and causing persistent diarrhea. The disease afflicts an estimated 450,000 Americans annually, killing 15,000. Most pick up the infection in hospitals and nursing homes.
The offending microbes are themselves increasingly resistant to conventional antibiotics. A fecal transplant is often the last resort.
The donor’s stool is introduced into the intestine or colon of a sick patient via an enema, colonoscopy or nasogastric or nasojejunal tubes. The healthy bacteria appear to displace C. difficile and re-establish a normal microbial community in the gut.
But transplants are expensive, time-consuming and invasive. “The first thing we started thinking about was, we need to get rid of the colonoscopy,” Smith said.
Two studies showed that encapsulated pills, in frozen and freeze-dried form, were effective in treating recurrent C. difficile. But it was not clear how to produce the capsules in large quantities.
“It’s got to retain viability,” Smith said. “It’s got to all be done at room to body temperature.”
The active biological ingredient posed a particular challenge. Capsules are often designed to dissolve in feces; filled with it, the pills essentially degrade from the inside out.
After more than a year and a half, OpenBiome finally developed capsules made with a microbial emulsion that traps tiny droplets of bacterial cells in an aqueous fat. As a result, the pills remain solid at room temperature, then liquefy and dissolve in the upper small intestine.
In a pilot study, presented last month at a scientific meeting in Europe, clinicians showed that swallowing a single dose of 30 capsules cured 70 percent of patients with C. difficile infections. When uncured patients were re-treated with a second dose, the cure rate rose to 94 percent.
In previous studies, by comparison, fecal microbiota administered via colonoscopy has been shown to be about 90 percent effective in curing C. difficile infection; antibiotics tend to be less than 40 percent effective. Currently, the new 30-capsule regimen is priced at $635 and is sold only to doctors. The pills are not approved by the Food and Drug Administration, but the agency has chosen not to take enforcement action because of the lack of alternatives.
Despite the improvement, the “pill burden” is substantial, and swallowing capsules filled with human feces is not without risk. Get potentially lifesaving gut microbes into the lungs, for instance, and the treatment could prove fatal.
Some suspect healthy human stool eventually may not be necessary at all. Seres Therapeutics, a Cambridge, Massachusetts, biotechnology company, is conducting Phase II clinical trials of SER-109, a four-pill regimen made from spore-forming anaerobic bacteria extracted from donated human feces and treated with ethanol.
According to Dr. Roger Pomerantz, the chief executive of Seres, the company also has a second-generation pill that comprises similar microorganisms grown synthetically in the laboratory. He does not see a future for pills containing actual feces.
“I don’t see why anyone would do it,” Pomerantz said. “I can’t believe the future is sending feces around the country.” At the moment, however, these new formulations are still under development, and there is no alternative.
Smith and his colleagues say encapsulated pills will help expand research. Clinical trials around the country, and the world, are testing the fecal microbiota transplants against not just C. difficile, but other gastrointestinal ailments.
Dr. Jessica R. Allegretti, a physician at Brigham and Women’s Hospital in Boston, is putting together trials of the capsules against Crohn’s disease, obesity and primary C. difficile.
“It really does reduce the time from evaluation to procedure. It really does broaden who can get treated on a much larger scale, and for that, capsules are the wave of the future,” she said — especially, she added, for disorders that appear to require multiple treatments, or “maintenance” doses.
“What capsules are allowing us to do is really pursue these long-term studies, long-term maintenance therapy, which is more practical for these chronic diseases,” she said. “Without capsules, we wouldn’t be able to do this kind of work.”