New Therapies for C. difficile in Development
Tolevamer (Genzyme Corp.) is a high-molecular-weight polymer that binds the C. difficile toxins A and B, thus representing a potential nonantibiotic therapy. It failed to meet criteria for noninferiority to vancomycin in its first phase III study, presented at the 2007 ICAAC meeting. Still, the recurrence rate for tolevamer (3.4%) was significantly lower than for vancomycin (23.4%) or metronidazole (27.1%), suggesting that this agent could prevent relapse in patients who are able to stay off antibiotics, Dr. Gerding said.
Phase II data on the neutralizing monoclonal antibody to C. difficile toxin A, developed by Massachusetts Biologic Lab and Medarex Inc., were presented in a poster at the 2008 ICAAC/IDSA meeting. There were no differences in recurrence among 29 patients who received the agent, compared with 17 receiving placebo (17% vs. 18%), but recurrence of disease was associated with significantly lower concentrations of antitoxin B antibody, suggesting that both toxins need to be targeted.
The companies are now conducting phase II trials of antitoxin A and B human Mabs as an adjunctive treatment and for the prevention of recurrence. In one such phase II study of 200 patients treated with vancomycin or metronidazole and randomized to Mabs against toxin A and toxin B versus placebo, there was a 70% reduction in recurrence with the Mabs, Dr. Gerding said in the interview.
Also targeting the two toxins is a toxin A/B toxoid vaccine made by Acambis PLC, which has completed phase I immunogenicity and safety trials and is undergoing phase II trials for patients with recurrent CDI in the United Kingdom.
Finally, Dr. Gerding outlined his own work on toxigenic C. difficile, a product he is working on in collaboration with ViroPharma Inc. The idea is based on work initially done 2 decades ago, in which prior colonization of clindamycin-treated hamsters with nontoxigenic strains of C. difficile protected them from subsequent colonization with a toxigenic pathogenic strain (J. Med. Microbiol. 1985;19:339–50). More recent work again showed that colonization with nontoxigenic CD strains is highly effective in preventing CDI in hamsters challenged with toxigenic CD strains (J. Infect. Dis. 2002;186:1781–9).
Similarly, Dr. Gerding's work has shown that, in hamsters that have been treated for CDI with vancomycin, giving a nontoxigenic CD strain followed by a toxigenic strain protected 9 out of 10 hamsters from relapse, compared with 0 of 5 that had not been pretreated. Human trials are set to begin in early 2009. “To the extent that hamsters are like humans, we may have something going here,” he said.
Dr. Gerding holds patents for the treatment and prevention of CDI licensed to ViroPharma and is a consultant for and/or holds research grants from Genzyme, Massachusetts Biological Laboratories, GOJO Industries Inc., Optimer, Salix, Merck & Co., Cepheid, Schering-Plough Corp., and ViroPharma.
