Emerging Agents for the Treatment of Alzheimer Disease


Alireza Atri, MD, PhD: There are 2 programs that are either in late-stage or going into late-stage development with antibodies: BAN2401 and gantenerumab. In both of those cases…from earlier studies there are signals that there may be clinical benefit, and at least suggestion or signals that there may be amyloid removal. But again, given the complexity of this disease, these programs need to really go and read out for us to be able to say something. Each of these antibodies work in a different profile. While some of them work much more on the plaques or the fibrils, some of them will work more on the protofibrils and fibrils, and some will work across the spectrum. Given that, and because the criteria are different, I think there is still hope, even though that’s been sort of moderated with the recent failures.

The other approach that I mentioned explores BACE [beta secretase] inhibitors, that are still ongoing for amyloid. While there is enthusiasm for amyloid-related treatments being mitigated in the dementia stages of Alzheimer disease, what’s still a big area of exploration are tau-related approaches, including antibodies or aggregation agents.

And as I mentioned, there’s also a fair bit of work now on targeting specific inflammation, vascular brain injury, and also targeting the other components of proteins that may cause dementia syndrome. It’s not all related to Alzheimer disease. Aging factors and effects on the mitochondria are going to be important. There is still a vibrant group of drugs that are in development, and we still need to have the mobilization between neurologists, our patients, clinicians, industry, the government, and biopharma because this is all our problem. Without actually doing these studies, we don’t really know the answers.

Beyond that, there are symptomatic approaches. There are individuals in moderate to severe stages of Alzheimer disease, where a lot of the new treatments are not being tested. We really do need treatments to add to our current treatments for those. Often with those individuals, I think what’s becoming more clear is that the approaches that are amyloid-related aren’t going to be working at that stage. We still need to find other approaches, including neurochemicals, to help them with symptoms.

Ronald C. Petersen, MD, PhD: The BAN2401 trial involves an antibody that is thought to get at the protofibrils in the Alzheimer amyloid cascade. So as you go from soluble to insoluble amyloid in the brain, protofibrils are kind of intermediate along that line. This antibody is designed to take that out of the processing step.

In a recent trial of BAN2401, the individuals who received the highest dose of that antibody actually had amyloid removed from the brain, and there was a suggestion of clinical stabilization, or perhaps improvement. This was a suggestion that this might be an effective treatment. So this company now, Eisai Co, is going to launch a new study using this agent to see if we can remove the amyloid from the brain and have a clinical outcome that is beneficial.

The use of BAN2401 is somewhat controversial because all of the other trials aimed at symptomatic people—that is people with mild cognitive impairment or people with mild dementia due to Alzheimer disease—have largely failed. BAN2401 is looking at that same population of people with mild impairment, and whether it’s reasonable to go forward. However, others indicate that this antibody may be a bit more specific, again, for the protofibrils in the amyloid cascade, and therefore, may be beneficial, and is presumably safe.

Now, all of these antibodies run the risk of producing a condition called ARIA [amyloid-related imaging abnormalities], which are microhemorrhages or a little bit of edema in the brain thought to be due to breakdown of the blood-brain barrier, and substances seeping into the brain as a function of the antibody actually removing amyloid from the blood vessel wall. ARIA is being followed very carefully. It can be monitored by MRI [magnetic resonance imaging], and you can adjust the protocol and all. While it’s something to monitor for, I don’t think it’s something that’s necessarily going to defeat the trial before it starts. So people are saying that this may still be a viable approach to treating people with mild symptoms due to Alzheimer disease.

For patients who are symptomatic, BAN2401 might be offered to them, with all the caveats that many of the other trials with the same patient population have failed. What are the risks? What are the benefits? Let the patient and family decide as to whether they want to enter into the trial.

Gantenerumab is another antibody that is designed to remove the aggregated forms of amyloid from the brain. It’s gone through several early trials, and they were ineffective, but perhaps the dose was inappropriate? So what the individuals doing these trials have done is increased the dose of gantenerumab, and I think it does remove amyloid from the brain, like several of the other antibodies. But the key question is: Is there going to be a clinical accompaniment to that? Are people going to stabilize, maybe get better, but at least stabilize clinically?

Some of the recent disappointment in the file of Alzheimer therapeutics has risen from the failure of the 2 aducanumab trials. These trials were designed, again, to remove the aggregated form of amyloid from the brain. Preliminary data from a study from 3, 4 years ago indicated that the antibody was quite effective at doing what it was supposed to do—removing amyloid from the brain. So if you do serial PET [positron emission tomography] scans on people, you can see the amyloid being taken out of the brain and the actual total amount is reduced as you go further into the trial.

Now the million-dollar question has been: Does it make any difference clinically for these individuals? Unfortunately, just recently, the data safety monitoring committee for this study did a futility analysis, meaning that they assessed the likelihood that the trial could be positive if carried out to its full extent. They came to the conclusion that it apparently could not. We should stop the study at this time and not risk patient safety any longer. The study is not going to be positive.

Now, they looked at 1 aspect of the data, which is very important, and they probably came to a reasonable conclusion. But the supporters, the sponsors of this study need to drill down into the database and look at it much more carefully to see if there are any signals. While we say these trials fail, we learn a great deal from them. They may inform us about designing the next trial.

The class of drugs called BACE inhibitors has been investigated rather aggressively in the last year or so. At a recent meeting in Europe at the end of 2018, 3 of the drugs by different companies reported failures to do what they were supposed to do and actually may have had some adverse effects that were bothersome—cognitive worsening, and maybe some psychiatric symptoms were appearing. So all 3 of these trials were halted.

There are still a couple left, and elenbecestat is one of them. It has been monitored closely for these adverse effects, and at this point it appears that this particular compound is not producing those adverse effects. Whether it’s producing any benefit is a whole other issue. But elenbecestat is one of the BACE inhibitors that is going forward now in some of the newly designed trials.

I think the FDA is very primed to approve a drug for Alzheimer disease if, in fact, it can be shown to be efficacious. So I think the FDA will fast-track a variety of drugs, which will move the process of approval through much more rapidly. Then we’ll follow the drugs carefully post-approval to make sure there are not problems with them. But I think the FDA is a partner in trying to develop effective therapies for Alzheimer disease.

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video 4 - "Amyloid Cascade Hypothesis of Alzheimer’s Disease"
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Anton P. Porsteinsson, MD
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