Dr. Cohen shares factors that may have contributed to the high failure rate of Alzheimer’s disease clinical trials thus far.
Marwan Sabbagh, MD: Let’s move into treatments in the therapeutic landscape. I’m going to ask you the first question, Dr Cohen. The path to new treatments—all 4 of us have been involved in those developmental pipelines—has been difficult. What has led to the high failure rate in clinical studies, as far as you can tell?
Sharon Cohen, MD, FRCPC: It’s been tough slogging, but we’ve learned a lot. [One thing we’ve learned is that trials have likely failed because] we haven’t biologically characterized the participants. Until recently, we enrolled patients in trials who met syndromic criteria for Alzheimer disease or for MCI [mild cognitive impairment] due to Alzheimer. But for many, we saw them initially with subgroups of bapineuzumab trials and later with the requirement to confirm pathology or pathobiology for inclusion into a trial. Many individuals didn’t have amyloid and didn’t have Alzheimer disease. We were giving the drug to individuals who didn’t have the disease, hoping it would target Alzheimer. That led to refinements in how we characterize our patient population.
Another key learning was that we need to get the dose right. The idea of targeting amyloid was interesting. But if we weren’t demonstrating that we were lowering amyloid sufficiently, then even the best antiamyloid agent is doomed to fail because not enough is getting into the brain and not enough amyloid lowering is happening. We have the ability to raise the dose, balance risk benefit, and document target engagement and how much lowering. This has become important in this stage of Alzheimer drug development. We’re trying to be much more precise in determining which patients will benefit. They need to be amyloid positive. We need to go earlier; that’s another factor. It’s probably too late when tau, neuroinflammation, and other factors are the key drivers of disease and we’ve missed that opportunity to clear amyloid early.
All these learnings give us better clinical trial designs and hypothesis testing. We’re now including patients in trials who have a biologic marker of the disease. In some instances, that’s amyloid PET [positron emission tomography] positivity or a CSF [cerebrospinal fluid] amyloid positivity. But in some trials, it’s even more precise. It’s amyloid positivity but also tau, and maybe an intermediate level of tau. We’re heading toward this precise segment that we’re treating. It’s like the oncology model of treatment.
Transcript edited for clarity