by Michael Jorrin, "Doc Gumshoe" | August 15, 2018 10:44 am
Is this going to be good news, or bad news, or somewhere in between? On balance, I would say good news, simply because the research and investigation is going on at an intense pace. Currently there are 1,903 clinical trials underway at some stage, in the US and all over the world. When I first wrote about Alzheimer’s, back in 2014, that number was 1,286, so that’s a significant uptick.
The huge majority of the drugs in those clinical trials are in the earliest phases; however, 32 drugs are now in Phase 3 trials, with several different targets including amyloid plaque, neurotransmission, insulin/glucose, Tau protein, and others. Another 58 drugs are in Phase 2, with those same targets plus vascular issues, inflammation, and neuronal/synaptic growth. The projected launch dates for those 32 drugs in Phase 3 trials extend to 2025.
As for the 58 drugs now in Phase 2, the projected launch dates for all of these begin in 2022 and go all the way to 2028. Some of these drugs are already approved for other diseases and conditions, and the trials in these drugs are to learn if they might have some kind of beneficial effect on AD.
In my opinion, this does not hold out promise of a single “magic bullet” that will cure or reverse AD, removing it forever as a subject of concern. Instead, what it looks like is the confident expectation that a range of approaches will essentially render AD much more manageable. Some of the mechanisms may indeed slow the blizzard of amyloid plaque or neurofibrillary tangles which are now thought to be the underlying pathologies of AD. Others may encourage the formation of more new neuronal pathways in our brains, so that despite that blizzard, some avenues continue to be open. This happens all the time anyway; that’s how we form new memories and new associations. But perhaps that function can be assisted.
What I would consider to be bad news, possibly the worst news imaginable, is if were the case that the medical / scientific community had come to the conclusion that Alzheimer’s disease and dementia are normal and inevitable signs of aging, like grey hair and wrinkles, and that there wasn’t much to be done about it. But clearly, the general view is that AD will turn out to be manageable in some way – either treatable, or perhaps preventable.
Obviously, some of the impetus for this activity is a desire to locate the pot of gold, and a very rich pot that would be. If a drug company happened to hit on an agent that significantly delayed the dementia that accompanies AD, just about everyone on the planet would be pretty interested when they got to be about 60 years old. So even if pharma companies don’t have a clear path or a logical mechanism of action, they may be willing to pursue the slightest hint that a particular molecule may be the key to stopping AD.
Here are the figures on AD as of this year:
When people think about Alzheimer’s disease, dementia is the defining characteristic. But not all forgetfulness or absent-mindedness is dementia or related to Alzheimer’s disease. Being unable to summon up the name of a person you met at a party, or not remembering the precise word you want, or misplacing your cell phone, are not signs that you’re succumbing to AD. People with early AD who have memory lapses frequently forget that they had memory lapses in the first place. As time goes on, they may become confused, angry, sometimes apathetic, frightened, and paranoid. They wander, easily get lost, and may fail to recognize a spouse or a child. Ultimately, large parts of their brains essentially stop functioning. A common cause of death in AD patients is that they lose the capacity to swallow food; when they are fed, the food, rather than going down the esophagus into the stomach the way it’s supposed to, instead is aspirated into the lungs, leading to choking or pneumonia. When the brains of AD patients are examined on autopsy, they are frequently greatly shrunken. Large parts of the brain have actually been destroyed by the disease.
As you can see, the stakes are extremely high.
A stumbling block
There are many obstacles in the path to getting a potential AD drug through clinical trials and regulatory approval and, finally, to market. One of the most stubborn is simply recruiting enough subjects in the needed clinical trials to arrive at a meaningful result. Consider the requirements: the study subjects need to have confirmed AD, not simply show signs of dementia. But the dementia should not be so advanced as to make it difficult to detect improvement in these subjects. At first glance, those should not be insurmountable obstacles. Whereas formerly, AD could only be confirmed with certainty based on autopsies, it is now possible to confirm AD based on brain scans. So why don’t we just examine everybody who gets to the age of 60 by means of PET (positron emission tomography) scans and analysis of cerebral spinal fluid? That would identify a lot of people with early stage AD, likely before many of them became significantly demented, so it would be possible to test a drug to see if it delayed or stopped the progression of dementia.
At first glance, that sounds like a rational plan. After all, women get mammograms to avoid breast cancer and men get PSA tests to avoid prostate cancer. The difference is that we can provide assurance to those women and men that by means of early testing, they can avoid the worst consequences of those cancers with a high degree of certainty. But we cannot reassure 60-year olds that, if they take those brain scans, we have the means to help them avoid AD and dementia. So why on earth should they submit themselves to brain scans and having samples of their cerebrospinal fluid tested, if there’s no clear treatment as a result? And, do they really want to learn the dismal news?
If early stage AD is what we want in our study subjects, maybe we could just enroll people at the very first sign of dementia, when they forget the name of the capital of Upper Volta or the composer of the opera Hansel and Gretel. But do those individuals actually have AD? The likely answer is “No.” Older people do indeed forget things, perhaps because the hundred trillion neurons in their noggins are already crammed with a lifetime of details to remember. And if they should happen to ask their doctors whether they might be succumbing to AD, chances are their doctors would reassure them that, indeed, incidents of forgetfulness are by no means certain indicators that AD was closing in, and that they need not over-worry. Their doctors have good reason to take that course. One is that minor forgetfulness is very common as the years roll on. But perhaps an even more fundamental reason is that even if these doctors did suspect early AD, they cannot at this point recommend any really effective treatment. So primary care providers are not likely sources of clinical trial subjects.
A result of this has been to skew the studies in AD towards treating subjects in whom the disease has already resulted in significant dementia. A positive outcome in these studies would be that a significant percentage of the patients taking the study drug would experience a significant improvement in cognition. A somewhat less positive outcome in these studies would be if patients on the study drug experienced significantly less decline in cognition than patients on placebo. In other words, the study drug stops or at least substantially slows the progression of dementia. That’s not nothing, but it’s by no means equivalent to restoring Grandma to “sharp as a tack.” And, so far, at least, clinical trial results with positive outcomes of that type have been exceedingly rare.
An underlying issue is that it’s at least possible that the brain damage done by the progression of Alzheimer’s disease in terms of cognition is to a large degree irreversible. The specific mechanism that underlies AD is at this point subject to investigation, and no consensus has been reached whether the culprit is the toxic form of amyloid beta (Aβ) or the proliferation of Tau protein in the form of neurofibrillary tangles, or perhaps still something else. I am not at this point going to go back and delve into the details of the conversion of the usual shorter form of Aβ into the toxic longer form or the arguments in favor of one mechanism or another. (If you want a bit more on that subject, the three previous Doc Gumshoe tracts on AD are in the archive.) But it’s certainly possible that many of the clinical trials in drugs that are intended to slow or possibly reverse the progression of dementia in subjects with established AD and considerable dementia may be doomed to failure, because they may be targeting a mechanism that in fact has nothing to do with the progression of dementia.
The focus of AD studies should ideally be on identifying patients with preserved cognition, but who are highly likely to become demented if the AD disease process continues unchecked.
One study in particular, currently underway, focuses precisely on such patients.
The Crenezumab Project in Colombia
Why in Colombia? It happens that there’s an extended family in Colombia who have an extraordinarily high rate of developing Alzheimer’s disease. About 5,000 persons have been found who share the same ancestry; they are all descended from the same individual who came from Spain in the 18th century. What makes this group of people unique is that about half of them have a mutated gene, labeled PSEN1 E280A (“presenelin 1”), which results in the deposition of extremely high quantities of the toxic Aβ very early in life – as early as their mid-twenties. Many members of this unfortunate family develop full-blown Alzheimer’s dementia in their 40s. This correlation is thought by most researchers in the field to be the strongest evidence yet that it is Aβ that causes Alzheimer’s dementia, and not one of the other putative causes.
A clinical trial, enrolling about 300 of the members of this family, will investigate whether starting treatment very early can prevent the formation of toxic Aβ and also prevent dementia. As of February of 2017, 252 subjects had been enrolled in the trial. The trial will run 260 weeks (5 years), so we cannot expect results any time soon. The trial will be placebo-controlled, and will compare two groups of family members who possess the mutated gene, as well as a third group, who do not possess the mutated gene. If persons in the placebo group begin showing signs of dementia, they will be crossed over to drug treatment. A detailed description of this trial was published in March 2018. (Tariot PN, Alzheimer’s Dement 2018 Mar 8;4:150-160)
The study drug in this trial is crenezumab, from Genentech. Crenezumab is a monoclonal antibody, a subtype of immunoglobulin G4, and it was selected for the study from a large number of candidate drugs because it is less likely to cause immune reactions leading to edema in the brain. It is an antibody both to the 40- and the toxic 42-amino acid Aβ chains.
The trial is funded in part by NIH, but primarily by Genentech, which obviously has a great deal to gain by its success. It has been classified as a registration trial by NIH, meaning that if it meets the objectives of significantly preventing the onset of dementia in these subjects who are currently healthy, crenezumab is likely to be approved by the FDA. The trial is part of the Alzheimer Prevention Initiative and is also supported by the Banner Alzheimer’s Institute.
What would the failure of this trial mean? Many knowledgeable observers think that a great deal rides on this trial – much more than the fate of this one drug and the fortunes of Genentech. If crenezumab significantly slows the deposition of Aβ, but the subjects in the trial nonetheless go on to develop Alzheimer’s dementia, the scientific community will basically have to go back to looking for another underlying cause for the disease. What this might be, who knows.
A possibly promising clinical trial
The results of this trial were only announced a few weeks ago, at the annual meeting of the Alzheimer’s Association. It was an 18-month Phase 2 trial in 856 subjects with established Alzheimer’s disease, although in the fairly early stages. The trial drug is identified as BAN2401, by Eisai (ESALY), comarketed with Biogen. BAN2401 is a humanized version of a mouse monoclonal antibody that binds to a soluble form of Aβ, termed protofibrils, reducing its toxicity, and in some cases preventing those Aβ protofibrils from inflicting cell death on neurons.
Three different dosages of BAN2401 were evaluated in the trial – 2.5 milligrams per kilogram (mg/kg) of the trial subjects’ body weight, 5.0 mg/kg; and 10.0 mg/kg, each given bi-weekly. Early results were discouraging, as the subjects receiving the two lower dosages – 2.5 mg/kg and 5.0 mg/kg – actually performed less well on cognitive evaluations than did subjects receiving placebo.
The trial was continued despite these early negative results. When the full 18-month trial was completed, the subjects receiving the highest dose of BAN2401 – 10 mg/kg bi-weekly – did considerably better than placebo-treated subjects, scoring 30% higher on one cognitive test and 47% higher on another cognitive test. The conclusion was that in the 161 subjects treated with the highest dose of BAN2401, cognitive decline was slowed significantly in comparison with the placebo cohort.
It has been pointed out that this trial was the first trial that linked an agent that targeted Aβ with any evidence of a beneficial effect on cognition. No treatment addressing either Aβ or tangles of tau protein has been approved in 15 years, since either of those two putative causes of Alzheimer’s disease was proposed.
The results of the BAN2401 are far from definitive. One important difference between the subjects who were given the two lower doses and those who received the 10 mg/kg dose that ultimately gave strong signs of being effective is that whereas only about 30% of the subjects in the high dose arm were carriers of the APOEε4 gene, between 73% and 91% of the subjects in the two other arms were carriers of that gene. That gene is a specific variant of the apolipoprotein gene, and it is present in as many as half to three quarters of persons with AD. Many individuals with this gene do not go on to develop AD, and there is certainly not a one-to-one correlation between APOEε4 and AD.
The APOEε4 gene is a strong risk factor, but no more than that. Thus, analysts have been reluctant to ascribe the differences between the lower doses of BAN2401 and the 10 mg/kg dose to the presence of the APOEε4 gene in a majority of the subjects that received the lower dose versus its absence in a majority of the subjects that received the higher dose. That disparity is not determinative, but certainly leads to head-scratching.
The next analysis of the BAN2401 trial will be presented at the CTAD (Clinical Trials in Alzheimer’s Disease), which will be held October 24th – 27th in Barcelona. As my mother said about a million times, “We’ll just have to wait and see.”
In the meantime, how are Alzheimer’s disease patients treated?
In the forty-plus years since AD was recognized as the most common form of dementia, only five prescription drugs have been approved by the FDA for treatment of AD. None of those five drugs reverse Alzheimer’s dementia or even stop the progression of dementia. The most they are able to do is slow its progression, and that delay is usually only temporary. Three of the five drugs are cholesterinase inhibitors. They are:
The mechanism of action of most of these drugs is inhibition of the enzyme acetylcholesterinase, which breaks down acetylcholine in the brain. Acetylcholine (ACh) is vital to brain function, enabling the activity of cholinergic brain cells. One of the things that happen in AD is a decline in the numbers of cholinergic brain cells, so any means of increasing the amount of circulating ACh is a potential boost in brain functioning.
Aricept (donepezil) is the most widely-prescribed of these agents, and is the only one approved by the FDA for treating AD patients whose dementia has progressed to advanced stages. Donepezil is available in a 10 mg dose, and recently an extended-release 23 mg formulation has been approved for patients who have been taking the lower dose formulation for at least three months.
Another mechanism being tried is the blockade of glutamate receptors in the brain. Glutamate is an excitatory amino acid, meaning that it stimulates neuronal activity, which is necessary for brain function. However, excess glutamate action may overstimulate neurons, leading to premature cell death. The one agent that employs this mechanism is memantine, marketed as Namenda by Forest, and also sold in a number of supplement forms. Memantine aims to block the N-methyl-D-aspartate (NMDA) glutamate receptor channel, and is reported to be moderately effective in mild or moderate Alzheimer’s dementia.
A combination of donepezil and memantine, marketed as Namzaric, has been approved for treatment of moderate-to-severe AD in patients who have been taking the 10 mg dose of donepezil and who are considered – at least potentially – likely to benefit from more intensive treatment.
The benefit to patients from any of these drugs is temporary. The Alzheimer disease process, whether the deposition of amyloid beta or the proliferation of tau protein tangles, is not affected by these agents. It is at least possible that therapy combining one of the drugs that slowed the progression of dementia with a drug that actually affected the underlying disease process might have a considerably more potent effect in combating AD, but no such combination therapy has been proposed at this point.
The side effects most frequently associated with the three cholinesterase inhibitors are nausea, vomiting, loss of appetitive, and increased frequency of bowel movements. Memantine is associated with headache, constipation, confusion, and dizziness. The memantine/donepezil combination, as one might expect, combines the side effects of those two drugs into one somewhat confusing package. I don’t know, for instance, how one would combine constipation with increased frequency of bowel movements, and I suspect that the compiler of the adverse effects dossier for FDA approval was doing little more than pasting together the verbal terms.
Any specifically good news we can point to?
I won’t call it good news, but at least it’s interesting news – little indications about future avenues (or tracks in the jungle?) that researchers can explore. Some of those avenues, including ones that previously looked highly promising, have led nowhere.
Take BACE inhibitors. BACE 1 (beta-site amyloid precursor protein cleaving enzyme 1) is thought to lead to the formation of beta amyloid (Aβ) in the brain, which in turn is thought to lead to the cognitive disability that characterizes Alzheimer’s. Therefore, inhibition of this enzyme should prevent or delay the symptoms of AD. Several big pharma outfits, such as Amgen, Merck, Novartis, as well as the Banner Alzheimer’s Institute were planning to conduct trials to see whether AD might be prevented by means of a drug in that class. So far, the results have ranged from inconclusive to negative; Merck suspended its trial before bringing it to a conclusion, because all indications pointed to a complete bust.
So when I parade these supposedly promising pointers to possibly successful treatment forms, please do assume that Doc Gumshoe is looking at them through narrowly-slitted eyes. He’s not pessimistic, just skeptical. Here are a few:
… and practical measures that may make it easier to manage AD
This was a law passed in Massachusetts last week, according to a story in the Boston Globe on August 13th. The law requires physicians, physician assistants, and nurses to undergo training in diagnosis, treatment, and care of patients with AD and other forms of dementia before they can obtain or renew their licenses. It requires physicians who have diagnosed AD in a patient to inform a family member or a legal representative about the diagnosis. And it mandates that all hospitals put into practice a plan for recognizing and managing patients with dementia. The deadline for this to take effect is October 1, 2021.
Why is this necessary? Simply because of the data. About half of Americans with AD have in all likelihood not been diagnosed, based on known prevalence data. But even more concerning, about half of Americans who have been diagnosed with AD have not been informed of the diagnosis, nor have their families. This, as I said earlier, is most likely because the diagnosing physician doesn’t want to lower the boom on a patient and his/her family, when the physician believes that there is little that can be offered in the way of help. And it is also likely that the physician is not entirely certain of the diagnosis.
The Globe story gives a sort of case study of a man who was hit with AD at an unusually early age, his mid-40s. His symptoms were severe from the start. He was initially diagnosed with depression, stress, and attention-deficit hyperactivity disorder. He took medications and underwent counseling and anger management disorder, with zero benefit. During this time, he continued to “manage” the family finances, with the result that the family was ruined. If he had been promptly diagnosed, he might have been able to understand what was happening to him, and his family could have been spared years of torturous uncertainty.
The reluctance of this fellow’s health-care team to utter the diagnosis of AD is understandable, but keeping patients and their families in a state of uncertainty is no form of kindness. If the AD diagnosis is communicated to those concerned persons, it may help to focus them on palliative care, without totally obliterating the possibility that something helpful may yet emerge.
* * * * * * *
In a Doc Gumshoe encyclical last November, I mentioned a lengthy Lancet paper that, among other things, assessed modifiable factors that were statistically and perhaps causally linked to Alzheimer’s disease. According to the authors, an important concept in slowing down dementia is a factor that they call “cognitive reserve.” This sounds fairly obvious – if you have more reserve of any faculty, including cognition, you can afford to spare more of that faculty than a person that has less of it to start out with. The Lancet paper identified a number of what they termed “Population Attributable Factors” (PAFs) which they thought were responsible for as much as 35% of the incidence of dementia. The study was based in part on observation of about 10,000 adults in the UK.
In early life, poor education (i.e., no schooling beyond 11th grade) may account for 8% of dementia incidence, while in the middle years, the principal PAFs are hearing loss (9%), hypertension (2%) and obesity (1%), and in late life the PAFs are smoking (5%), depression (4%), physical inactivity (3%), social isolation (2%), and diabetes (1%). It’s highly likely that a number of those risk factors overlap; for example, high-school dropouts are far more likely to be smokers than are college graduates, and hypertension, obesity, physical inactivity, and diabetes certainly do tend to go together. Other data, by the way, tend to corroborate the Lancet conclusions, e.g., a 19% increase in midlife obesity in China was accompanied by a similar increase in the incidence of dementia. Cause and effect? Coincidence?
The way it looks to me is that the entire health-care community is trying to outflank Alzheimer’s disease, and attack it, or at least confront it, on all sides, from the deepest investigations of the pathophysiology of the disease, to pragmatic trials of “what works and doesn’t work,” to common-sense observations of what life-style factors appear to be associated with AD. I am on the lookout for results, and I’ll pass them on to you.
Good fortune and good health to all! And keep those comments coming! Thanks, Michael Jorrin (aka Doc Gumshoe)
[ed. note: Michael Jorrin, who I dubbed “Doc Gumshoe” many years ago, is a longtime medical writer (not a doctor) who joins us to share an update on the world of health and medicine a couple times a month. He does not generally write about investments directly, but has agreed to our trading restrictions. He chooses his own topics, and his past articles can be found on his author page here.]
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