Antidiarrhoeal - tolevamer
The bacterium Clostridium difficile is an increasing problem, particularly in a hospital setting, and one of the major symptoms of C. diff infection is the diarrhoea that often results.
The bacterium Clostridium difficile is an increasing problem, particularly in a hospital setting, and one of the major symptoms of C. diff infection is the diarrhoea that often results.
It is generally treated with the antibiotics metronidazole or vancomycin, but resistance and recurrence limit their usefulness in the long term, and alternative strategies would be extremely useful.
US company Dynavax is developing a non-antibiotic treatment, tolevamer. This is a high molecular weight polymer that binds toxins, which is given orally. It binds noncovalently to C. difficile toxins A and B, and then neutralises them. This prevents the gastrointestinal damage the toxins cause that leads to diarrhoea, allowing the normal gut microflora to survive - antibiotic therapy tends to kill these beneficial bacteria as well as the pathogenic ones. It was initially developed as the sodium salt, but it is now being investigated as the potassium salt, as this should prevent hyperkalaemia caused by potassium in the gut being bound too. The two salt forms have similar preclinical profiles.
Several clinical trials have been carried out, including a Phase I study to evaluate its tolerability and safety.1 The double blind, randomised, placebo-controlled dose optimisation trial was carried out in 40 healthy male volunteers, who were given up to 15g three times a day. Tolavamer was well tolerated at all the doses studied, adverse events were mild and not dose related, and flatulence was the most common one experienced. There was a small decrease in potassium excretion at the highest dose.
In a multicentre, double blind, active controlled, parallel Phase II trial, 289 patients with mild to moderately severe C. difficile associated diarrhoea were given 3g or 6g a day of tolevamer in capsule form, or 500mg a day of the antibiotic vancomycin, for 14 days.2 The diarrhoea resolved in 67% and 58% of the patients given the two doses of tolevamer respectively, and 91% of those given the antibiotic. At the higher dose, the recurrence rate was lower at 7% compared with 19% of those given vancomycin. Slightly higher rates of hyperkalaemia were observed in the tolevamer groups.
An oral solution formulation has also been developed, and several Phase III trials are under way.