“Companies want their drug to be labeled as a disease-modifying agent as soon as possible,” she said in an interview. And because they are going for that, they are designing phase II trials that are long and costly but don't give them all the information they need.”
Ideally, when any agent finishes phase II, there should be clear evidence that it is safe and effective in the primary end point. “Neither tramiprosate nor tarenflurbil had a clear signal in phase II, and neither did bapineuzumab, although it at least had some signal,” she said.
Companies could also modify their research track to prove first that a drug confers symptomatic benefit, and then examine its possible disease-modifying properties. That is the path Medivation Inc. is following with dimebon–the only bright note in late-stage clinical trials this year. The obscure Russian antihistamine, thought to boost mitochondrial function, succeeded where the antiamyloids failed, significantly improving cognition, behavior, and function in Alzheimer's patients, although it did not modify disease progression.
“Dimebon probably is a disease-modifying drug, but proving this requires long-term studies,” said Dr. Doody, primary investigator on the phase II trial. “But many pharmaceutical companies fear that a drug will be priced too low if they go for symptomatic approval first without the disease-modifying work up front.”
Dr. Marwan Sabbagh, chief medical and scientific officer of Sun Health Research Institute, Sun City, Ariz., suspects that researchers might be looking at antiamyloids through the wrong end of the lens. Rather than a one-step cure, the compounds may be best used in primary prevention. “The problem is, we may be approaching it too late,” he said in an interview. “By the time you clinically manifest dementia, it might be too late for the drugs to help, even if they clear the plaques.”
Dr. Rachelle Doody says the phase II trial of bapineuzumab “at least had some signal” that the agent is safe and effective. Agapito Sanchez Jr./Baylor College of Medicine