Here's what lies ahead for an experimental drug that targets oligomers, a form of beta amyloid protein that binds to and destroys synapses in the brain.
Any Alzheimer’s drug under development has a complicated journey from formulation to clinical trials to potentially getting in the hands of patients. We spoke to Nick Izzo, Director of Screening at Cognition Therapeutics, about a drug called CT1812 that targets beta amyloid protein, which scientists believe contributes to the death and decline of nerve cells in Alzheimer’s patients. It’s currently undergoing clinical trials. Izzo says his team has found that reducing the protein improves cognitive decline in mice, a result they’re now hoping to replicate in humans.
- The new drug targets oligomers, a form of beta amyloid protein that binds to and destroys synapses in the brain
- Tests of the drug in mice showed that it cleared the beta amyloid from synapses
- Early clinical trials in Australia indicate the drug is safe but years from conclusive evidence
Being Patient: You’re trying to develop a drug that removes beta amyloid oligomers from the brain. What is an oligomer and why are you targeting them and not beta amyloid plaques?
Nick Izzo: Beta amyloid can stick together in different ways. One way is as a plaque, which is what happens when long sticky fibrils [fibers] of beta amyloid build up and get stuck to the brain tissue. These are insoluble so they don’t move around the brain. Beta amyloid also takes another, smaller form called an oligomer. “Oligo” means many. So many “mers” or proteins stick together but they don’t form these long fibers. These oligomers are soluble so they can float around in the brain and bind to the synapses of neurons. When beta amyloid oligomers bind to those sites, they cause the spines at the end of the neurons to retract and disappear. These spines make connections to adjacent neurons, which are the pathways that form memories, so you lose memories.
When our company was formed, the decision was made to focus on beta amyloid oligomers and not the fibrils [plaques] and look at how they bind to the synapses. This is because we know that people can have plaques in their brain but they’re not showing signs of dementia. A lot of different therapeutics have been shown to reduce the amount of plaques in the brain but we haven’t seen a significant improvement in people’s cognitive abilities in clinical trials.
Being Patient: How did you discover the drug?
Nick Izzo: We started out looking for drug-like molecules that would interrupt the process of beta amyloid binding to neurons. We tested hundreds of compounds to find some that might make those oligomers come off. We started the process in 2008, doing these experiments in cultures of cells grown in a dish. We quickly were able to go from there to testing them in mice. The mice have been genetically altered to have an elevated level of beta amyloid oligomers that are sticking to the neurons. We saw that when we gave them our drug the oligomers were kicked off the neurons and show up in the cerebrospinal fluid, which means that they’re leaving the brain.
Being Patient: You’ve started clinical trials for the drug. Where are you in the development process?
Nick Izzo: The first phase was pretty small. We were looking at drug levels and safety with healthy volunteers. In our case we gave people one dose a day for two weeks and monitored them over that period and then for a follow-up period after that. And we went up in dose there until we got to the target level we wanted to get.
Now we’re doing what’s called a Phase B study in Australia with people with mild to moderate levels of Alzheimer’s disease. It’s still a safety trial but we are doing cognitive testing before and after. Again, it’s a small number of patients and fairly short in duration, so whether or not we’ll be able to see something, we don’t know. But we think there might be a very rapid restoration of these synaptic connections because of what we have seen in our pre-clinical studies. So in this clinical trial we are taking samples of cerebrospinal fluid and seeing if we can detect the oligomers showing up in it.
Being Patient: You’re analyzing the results at the moment and if you find that the trial is safe, what happens then? How do you move forward?
Nick Izzo: We’re going to be expanding to do studies in the United States. We have an Investigational New Drug protocol from the Food and Drug Administration, which means they’ve reviewed all of the data we’ve gathered in the studies and given us the go-ahead to begin trials in the US. The goal there is to find out if there’s an effect. If we look at patients at a particular stage of the disease, and we treat them for a certain amount of time, can we see an improvement in their function or that their function isn’t declining anymore?
Being Patient: How many trials do you have to do before you get to the stage where you can bring a drug to market?
Nick Izzo: I think there we’re looking at many years. Because you’re talking about Phase II studies, and probably multiple Phase II studies. If you do one study, and you learn a little bit about it, and then you say, “Okay, well maybe we have to do it at a different dose”, or maybe a new method of detection comes along, and say, “OK, now we’d really like to do this study and be able to use this other tool to look for improvements,” so it takes time.