[ed. note: Michael Jorrin, who I like to call “Doc Gumshoe,” writes about health and medicine for us from time to time. His columns are not generally focused on investments, though this one does include some commentary about a number of specific companies (most are not publicly traded). His words and opinions are his own, and he has agreed to our trading restrictions. Enjoy!]
The campaign to do something about Alzheimer’s disease (I won’t call it a war) moves forward on several fronts – forward, but with pretty frequent setbacks. We have to acknowledge that at this point, after having tried literally thousands of approaches, no drug or treatment modality reverses the course of the disease. That doesn’t mean that reversing or at least stopping disease progression is not the objective of a colossal amount of effort on the part of a great many entities of all types – academic centers, big and not-so-big pharma, biotechs of all sizes, government, foundations, and some individual scientists.
But it does mean that there is also a great deal of research into drugs and treatments that are not disease-modifying, but can to some degree mitigate the effects of Alzheimer’s disease (AD), specifically in the area of cognition. And, because the optimum time to start treating a person with AD would be as early as possible in the course of the disease so as to prevent irreversible cognitive damage, there is also a great deal of research directed at finding markers that could identify AD in the earliest stages.
In a way, the AD landscape resembles what was going on in rheumatoid arthritis treatment when I first started doing projects in that area. As in AD, there were no disease-modifying agents for RA; the best that could be hoped for was managing the patient’s worst symptoms as the disease marched on, leaving many patients severely disabled. Symptom management relied heavily on high-dose aspirin (this was before even ibuprofen became commonly available) with perhaps a steroid shot if Grandma wanted to get out on the dance floor at her grand-daughter’s wedding. A major difference is that current understanding of what happens in AD at the cellular and molecular level is far ahead of what was known about RA in those bygone days.
The short take is that even though there are no Alzheimer’s disease-modifying drugs available yet, the picture is not bleak. There are options that to some degree mitigate or delay cognitive decline in AD patients, and there are some strategies that appear to affect what are at least assumed to be some of the underlying causes. So there is hope!
How is treatment benefit in AD measured?
I trust that doesn’t sound like a dumb question. I can imagine loud answers from all quarters, amounting to, “If the treatment slows or reverses dementia, that’s a clear positive.” Yes, of course, I agree with that. A question is, are there any really objective and accurate ways of measuring the degree of dementia? And, yes, of course, when the husband fails to recognize his wife, that’s not so good (but remember that excellent book by Oliver Sacks, The Man Who Mistook His Wife for a Hat). But what about finer distinctions?
What they use in clinical trials to assess dementia, or the absence of dementia, are “validated instruments,” – i.e., the Mini Mental State Examination (MMSE), the Clinical Dementia Rating – Sum of Boxes (CDR-SB), and the Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog). These, and others, are widely used and widely accepted. However, what is missing is an independent, objective measure. When an infection is being treated, it’s one thing when the symptoms go away, but you can always test to see if the pathogen has been vanquished. Currently, there is no such test in AD. Brain scans can detect the presence of amyloid plaque and analyses of cerebrospinal fluid can test for amyloid beta (Aβ) and tau protein, and these tests certainly provide valuable corroborative evidence, if not definitive proof. Also, many of the early-stage studies are not in humans, but in laboratory animals. There are supposedly ways of testing the cognitive capacities of mice – do they remember where the cheese is hidden? – but I hope I can be forgiven for questioning their reliability.
So let’s start out by checking on developments regarding the eleven pharmaceutical companies that I described in my 2013 piece, “Current Clinical Trials in Alzheimer’s Disease.” I am listing them by sponsor rather than by the name of the agent, mostly because several of the agents don’t have names as yet. And, as you’ll see, for several of these outfits, the news is not good, or, in some cases, there’s no news at all. I’m including the whole list as witness of the stuttering progress of investigational drugs for AD.
Broomfield, CO 80021
Accera’s AC-1202 is a medium-chain triglyceride that is metabolized into ketone bodies which provide nutrients to the brain. One of the hallmarks of AD progression is that the brain is prevented from using blood glucose for energy; AC-1202 is supposed to compensate for that. It’s marketed as a pharmaceutical under the name Ketasyn, and as a nutritional supplement as Axona. An agent with a similar mechanism, AC-1204, has enrolled about 75% of 480 subjects in a Phase 3 clinical trial, NOURISH-AD. Another Phase 3 trial is in the works.
This approach does not address the underlying disease process in AD, but likely has merit in slowing dementia. Researchers are looking into the possibility of using nasal insulin to boost glucose utilization in the brains of persons with AD, and the nutritional supplement faction has been quick to point out that the medium-chain triglycerides in Ketasyn and Axona are also present in coconut oil, so that might be a helpful dietary supplement.
Alzheimer’s Disease Cooperative Study (ADCS)
(in cooperation with the National Institute of Aging)
San Diego, CA
The resveratrol trial that I mentioned back in 2013 now has results, and they are at least somewhat promising. Resveratrol’s supposed mechanism is that it stimulates the activity of a class of enzymes called sirtuins, which are thought to mimic the anti-aging effects that caloric restriction has demonstrated in animals. This was supposedly why red wine drinkers (red wine, you certainly know, contains resveratrol) get a survival benefit – although the amount of resveratrol contained in red wine is nowhere near the amount that has been used in clinical trials. The Phase 2 trial enrolled 119 subjects with mild-to-moderate AD and assessed levels of amyloid beta (Aβ) 40 and 42 as well as tau protein in the cerebrospinal fluid. As you may remember from my previous piece, a higher proportion of Aβ42 to Aβ40 is associated with the progression of AD dementia. In this trial, patients taking up to 2000 mg of resveratrol per day maintained higher levels of Aβ40 (which we might dub “the good amyloid beta”) in proportion to Aβ42. There were no differences in tau protein, nor in the mini-mental state exam, but the treated subjects performed better on the activities of daily living scale. All in all, these results, published in September 2015, encourage further research.
Bellus Health, Inc
Laval, Quebec, Canada, H7V4A7
Bellus’s principal candidate is Alzhemed, which is also marketed as a neutraceutical under the name Vivimind. Alzhemed is also known as tramiprosate and as homotaurine, and sometimes as 3APS. The supposed mechanism of action is that it binds to soluble Aβ, inhibiting formation of the sheet formations of Aβ that are found in Alzheimer’s patients. Clinical trials in this agent have failed to show any benefit thus far. Vivimind and another related agent, BLU8499, were licensed to a US company, Alzheon, in late 2013.
[ed. note: Bellus Health is tiny but publicly traded, BLU in Canada, and BLUSF OTC in the US.]
Biogen Idec (BIIB)
In March 2015, Biogen’s AD drug, formerly BIIB037, now aducanumab, reported positive interim results in the PRIME study, a Phase Ib trial. What is particularly arresting about these results is that BIIB037/aducanumab is the first AD agent that has demonstrated both significant symptomatic benefit and significant benefit with regard to one of the presumed physiologic causes of AD, namely the deposition of amyloid plaque. BIIB037/aducanumab is a human recombinant monoclonal antibody (mAb) that targets aggregated forms of Aβ. The original antibodies on which the mAb is modeled came from the brains of individual donors who were thought to have successfully overcome AD.
The trial enrolled 166 patients with mild forms of the disease and followed them for one year. The symptomatic measures employed were the MMSE and the CDR-SB. Four dosage levels of BIIB037/aducanumab were assessed, and at the highest dose, subjects lost 0.58 points on the MMSE, while subjects on placebo lost 3.14 points. On the CDR-SB the scores were 0.59 points for BIIB037 versus 2.04 for placebo. Both differences were statistically significant.
Amyloid plaque deposition was measured by PET scans using the radiotracer florbetrapir 1, which binds to amyloid. In the two highest BIIB037 dose levels, 6 and 10 mg per kg of body weight, the differences in plaque deposition compared with placebo were both considered highly significant, P < 0.001. Another trial in the 6 mg/kg dose failed to reach clinical significance, which was considered a setback in the development program for aducanumab. Assessing dose levels lower than the 10mg/kg dose is important, because of a dose-relate