Emerging agents for the treatment of Alzheimer's disease

Alireza Atri, MD, PhD: Two programs are in the late stage or advanced stage of development with antibodies: BAN2401 and gantenerumab. In both cases … previous studies indicate that clinical benefits can be observed, and at least one suggestion or signals indicating that amyloid elimination is possible. But again, given the complexity of this disease, these programs must really allow us to read so that we can say something. Each of these antibodies has a different profile. Some work much more on plates or fibrils, but some will work more on protofibrils and fibrils, and others on the whole spectrum. Given that and the fact that the criteria are different, I think there is still hope, even if it has been moderated with the recent failures.

The other approach that I mentioned explores BACE [beta secretase] inhibitors, which are still going for amyloid. Although amyloid-related treatments are attenuated during dementia stages of Alzheimer's dementia, tau-related approaches, including antibodies or aggregators, are still an important area.

As I mentioned earlier, there is also a lot of work going on to target specific inflammation, vascular brain damage, as well as to target other components of the proteins that can cause dementia syndrome. Not everything is linked to Alzheimer's disease. Aging factors and effects on mitochondria will be important. A dynamic drug group is still in development and we still need to mobilize neurologists, our patients, our clinicians, industry, government and biopharmacy because that is our whole problem. Without these studies, we do not really know the answers.

Beyond that, there are symptomatic approaches. There are individuals in the moderate to severe stages of Alzheimer's disease, where many of the newer treatments are not tested. We really need treatments to complement our current treatments. Often, with these people, I think what is more and more clear is that amyloid-related approaches will not work at this stage. We still need to find other approaches, including neurochemicals, to help with the symptoms.

Ronald C. Petersen, MD, PhD: The BAN2401 baday involves an antibody that is thought to attack the protofibrils of the amyloid Alzheimer's cascade. So when you go from soluble amyloid to insoluble in the brain, protofibrils are sort of intermediates along that line. This antibody is designed to remove this from the treatment stage.

In a recent trial on BAN2401, people who received the highest dose of this antibody had amyloid removal from the brain and suggested clinical stabilization or even improvement. It was a suggestion that this could be an effective treatment. So, this company, Eisai Co, will launch a new study using this agent to see if we can eliminate amyloid from the brain and get a beneficial clinical outcome.

The use of BAN2401 is somewhat controversial, as all other tests intended for symptomatic individuals, namely people with mild cognitive impairment or people with mild dementia due to Alzheimer's disease, have largely failed. BAN2401 is looking at the same population of people with mild disabilities and it is reasonable to move forward. However, others indicate that this antibody might be a little more specific, again, for protofibrils in the amyloid cascade, and therefore, could be beneficial and probably safe.

Now all these antibodies run the risk of producing a disease called ARIA [amyloid-related imaging abnormalities], microhemorrhages or a bit of edema in the brain, presumably due to rupture of the blood-brain barrier, and substances infiltrating into the brain depending on the antibody actually eliminating the Amyloid of the wall of the blood vessels. ARIA is followed very carefully. It can be monitored by MRI [magnetic resonance imaging], and you can adjust the protocol and everything. While this is something to watch out for, I do not think it will be something that will necessarily cause the trial to fail before it starts. So, people say that this could still be a viable approach to treating people with mild symptoms due to Alzheimer's disease.

For symptomatic patients, BAN2401 could be offered to them, with all the caveats that many other trials involving the same patient population have failed. What are the risks? What are the benefits? Let the patient and family decide whether or not to participate in the trial.

Gantenerumab is another antibody designed to eliminate aggregated forms of amyloid from the brain. It was the subject of several preliminary tests and they were ineffective, but maybe the dose was inappropriate? The people who participated in these trials therefore increased the dose of gantenerumab and I think it eliminates the amyloid of the brain, like several other antibodies. But the key question is: will there be clinical support for this? Will people stabilize, maybe get better, but at least stabilize clinically?

Part of the recent disappointment regarding the Alzheimer's disease treatment file is due to the failure of the two trials on aducanumab. These tests were aimed once again at eliminating the aggregated form of amyloid in the brain. Preliminary data from a study conducted 3 or 4 years ago showed that the antibody was effective enough to do what it was supposed to do: eliminate amyloid from the brain. So, if you make PET in series [positron emission tomography] scans on people, you can see the amyloid being removed from the brain and the actual total amount is reduced as you go through the test.

Now, the million dollar question is this: does it make a clinical difference for these people? Unfortunately, just recently, the Data Security Oversight Committee of this study conducted a futility badysis, which means that it evaluated the likelihood that the test could be positive if it was realized in all its magnitude. They came to the conclusion that it apparently could not. We must stop the study for the time being and not risk the safety of patients. The study will not be positive.

Now they've looked at one aspect of the data, which is very important, and they've probably come to a reasonable conclusion. But the supporters, the sponsors of this study must deepen the database and look at it a lot more closely to see if there are any signals. Although we say that these tests fail, we learn a lot. They can inform us of the design of the next test.

The clbad of drugs called BACE inhibitors has been fairly aggressively researched in the last year or so. At a recent meeting in Europe in late 2018, three of the drugs from different companies reported breaches of duty and had some uncomfortable side effects: cognitive worsening and possibly psychiatric symptoms. appearing. So, all 3 of these trials were stopped.

There are still a couple left and elenbecestat is one of them. These adverse effects have been closely monitored and at this stage it appears that this compound does not produce these undesirable effects. Whether it produces any benefit is a different problem. However, elenbecestat is one of the BACE inhibitors that is currently being retested.

I think the FDA is quite ready to approve a drug for Alzheimer's disease if it is actually effective. So I think the FDA will speed up the processing of various drugs, which will greatly speed up the approval process. Then we will carefully monitor the drugs after approval to make sure they do not cause any problems. But I think the FDA is a partner who is trying to develop effective treatments for Alzheimer's disease.