I came across this article through the Cure Alzheimer’s fund website. While I am happy to spread the word on success in research on treating dementia, I also want to be sure people get the full story and not just the happy headlines 🙂
The jist of the research is that the pharmaceutical company Biogen, with headquarters in Cambridge, Massassachutes in USA, has designed a new drug based on processes that naturally occur in our bodies. This drug, Aducanumab, is a reproduction of our bodies own beta-amyloid autoantibodies, which are natural antibodies to amyloid beta, or Abeta, (amyloid beta creates the misfolded pepetides – which become the plaques – in Alzheimer’s disease).
The really amazing thing is that they find that the drug could potentially prevent the development of any Alzheimer’s symptoms if administered early enough in the disease process. The study showed that the amyloid plaques initiate Alzheimer’s disease by causing the neurofibrillary tangles to form and inflammation in the brain. So, the study suggests that if you can stop the amyloid beta from accumulating in the brain, you can slow down or stop Alzheimer’s disease.
These autoantibodies are found in the cerebrospinal fluid of healthy individuals, and are believed to reduce not only existing plaques, but to also prevent further development of plaques in the brain. People who have Alzheimer’s also have these Beta-amyloid antibodies, but some research shows that they have a significantly lower number than healthy people, while yet other research shows they may have much higher levels of the antibodies. (The reason it is hard to give a certain answer if the antibodies are higher or lower in Alzheimer’s diseased brains is because the antibodies and antigens are in a state of dynamic equilibrium between bound and unbound forms, and are concentration-dependent. Dynamic equilibrium means that the composition does not change, even though there are reactions and the substances move between chemicals at equal rate. This chemistry stuff is a bit hard for me to understand, too 😉 )
Biogen’s Swiss partner, Neurimmune, isolated the antibodies in people over 100 (centenarians) who still had very good cognitive abilities. They had thought that these centenarians were protected against Alzheimer’s disease because they have the potent antibodies. Biogen then developed the drug Aducanumab and tested it in 166 people, showing that the drug reduced amyloid in the brain and slowed cognitive decline over one year’s time.
Here is where I start to caution – Biogen’s study of 166 people was a Phase I clinical trial. This means that it is a safety trial, which is used to make sure that the medication does not cause more harm than good. If a treatment passes this phase of clinical testing, it moves on to Phase II, where they can test on many more people to determine if the treatment is beneficial. It is a very important distinction that, until a treatment passes Phase II testing, it is not assumed to have any therapeutic effect. It is not until a treatment passes a Phase III trial that it can actually be considered to be therapeutic. By the way, Biogen is going straight from a Phase I trial to a Phase III trial. In this light, it is very early to say that this new drug is effective or beneficial.
And here is where I get on my soap box:
There is a lot of research being done to prevent, reverse, or stop dementias – especially Alzheimer’s disease, which is the most common form of dementia. And the world is ready to hear about something that will help. So far, there is no drug or therapy that is shown to actually prevent, stop, or reverse Alzheimer’s or most dementias. But, the media is not as cautious as researchers in claiming that something has worked. They hear about a new drug or treatment that has shown some promise and go ahead an publish on it as if it is almost ready for the market and shown to be the magic cure we have all been waiting for. This gives false hope to a lot of people, is incorrect, and is actually quite unethical. Many people start to get jaded about research into dementias because they keep hearing about the latest miracle cure, which always turns out to actually not be effective, and people get upset at the researchers. But, dear readers, it is not the researchers who are driving this “We found a cure!”-train, it is the media. I have several friend who will email me articles and ask for my opinion on if this or that is going to be the new treatment for dementia and my answer is almost always the same after I do some digging around and read the actual research articles – it is too early to tell and the media has made this seem like a bigger deal that it is at this point.
Soap box rant over.
I suggest more caution about this new promising drug for 3 major reasons:
- This Biogen Phase I trial actually tested the new drug on 32 people (a VERY small number to determine if a drug is safe or not, especially considering the MILLIONS who have Alzheimer’s disease). They also tested at different doses and found that the slowing of cognitive decline was only present in those who had the highest dose of the drug.
- There were side effects, especially in those who had the highest dose (which was the only dose found to be effective) and in those who have the APOE4 gene for Alzheimer’s disease. While they report that the side effects tended to resolve themselves over time, they were brain swelling and headaches, which could be quite bothersome to anyone, but especially to people who are already having cognitive problems. As this article says, these side effects can also cause people to drop out of clinical trials before they can see any benefit. I also wonder how long it takes for the side effects to resolve themselves – one month, 9 months, one year?
- Additionally, when comparing the rates of cognitive decline in the people who took the drug and the people who took a placebo drug (the test group versus the control group), the results are significant when comparing the rate of cognitive decline between the two groups at the end of the trial. And, in this study, the results are skewed because the placebo group showed more cognitive decline than is normally seen in other studies. So, we really can’t say that the drug was so effective, as much as we can say that those who did not take the drug had more decline. That’s a big difference. And in the larger Phase III trial, it is likely that the placebo group will show more normal rates of decline and then the difference between those who take the drug and those who don’t will be much smaller – hardly a miracle cure.
However, they did use the MMSE cognitive test in the trial. This is, so far, the most common used cognitive test used in diagnosing dementias. However, it is better suited to Alzheimer’s disease and to detect larger changes in cognition. For other types of dementia and Mild Cognitive Impairment, as well as to measure smaller changes in cognition, the MoCA test is better. So, what we can determine from the results, is that the placebo group showed more of the larger changes in cognition than those who took the new drug (and more change than people who have Alzheimer’s in the general population).
Now that you have heard my rantings and warnings, please read the article and let me know what you think down in the comments.
Promising New Alzheimer’s Drug Validates Anti-Amyloid Approach
As reported recently in the New York Times (Business Day, March 20, 2015, “Biogen Reports Its Alzheimer’s Drug Sharply Slows Cognitive Decline”) and other media, the pharmaceutical company Biogen has announced impressive results in a Phase I “human safety” trial of a new drug designed to treat — and possibly prevent — Alzheimer’s disease. The drug, aducanumab, lowered brain Abeta levels and slowed decline in cognitive function compared to a control group of Alzheimer’s patients receiving a placebo.
“Hats off to Biogen — this is an extremely important breakthrough,” commented Rudy Tanzi, Ph.D., chair of the Cure Alzheimer’s Fund (CAF) Research Consortium. “It is the first trial showing that lowering Abeta levels in the brain can slow down cognitive decline in patients. It also nicely dovetails with several active CAF projects. Most importantly, it further validates our understanding of the disease, from genetic studies, showing that amyloid plaques initiate the disease by causing the formation of neurofibrillary tangles and inflammation. The Biogen study offers the first proof that if you can stop the accumulation of Abeta in the brain, you can slow down or even stop the disease in its tracks.”
Biogen’s new drug is a reproduction of a naturally-occurring human antibody that removes Abeta “plaques” from the brain, potentially stopping the disease from developing any further. If administered early enough, this approach could potentially prevent the development of any Alzheimer’s symptoms. We have known for years that the body produces naturally occurring antibodies to Abeta, called “beta-amyloid auto-antibodies”. In 2005, Dr. Tanzi and Dr. Robert Moir at the Massachusetts General Hospital Genetics and Aging Research Unit reported that auto-antibodies naturally made by the body to defend against clumped up aggregates of Abeta are depleted in Alzheimer’s disease. Meanwhile, they appear in higher concentrations in younger unaffected subjects. Based on these findings, Tanzi and Moir proposed in 2005 that since the naturally occurring antibodies were protective against age-related onset of Alzheimer’s when present in high concentrations, they could be a powerful therapeutic for treating and preventing Alzheimer’s disease.
The root studies of the new Biogen therapy, aducanumab, were carried out by their partner, Neurimmune, a Swiss Biotech company. The drug screen was based on seeking out the most potent naturally occurring auto-antibodies against Abeta deposits and then mimicking them to treat the disease. In a very clever approach, the Neurimmune scientists isolated the anti-beta amyloid antibodies from centenarians with remarkably intact cognitive abilities. The assumption was the centenarians were highly protected against Alzheimer’s because they possessed potent protective antibodies against Abeta, similar to those described by Moir and Tanzi in 2005. The bet paid off when Neurimmune’s partner, Biogen, announced in the completion of the Phase I clinical trial of 166 patients that their new antibody treatment reduced amyloid levels in the brain and correspondingly slowed down cognitive decline over the course of about one year.
While the new Biogen therapy shows great promise as it heads directly into a much larger Phase III “efficacy” trial, there are also some concerns, Tanzi noted. “While we are very excited and optimistic about the new Biogen therapy, there is still a lot of work yet to be completed and we cannot just assume that the next trial (Phase III) will be a slam dunk.”
First, the significant cognitive results using the specific memory tests that the FDA bases approval upon, came only from the highest dose group. There were 32 patients in this group versus 40 patients on placebo. “These are still small numbers,” Tanzi said. “so, while we are very hopeful, is not guaranteed that the results will be replicated in the larger Phase III trial.”
Second, the placebo group had a larger decline in cognition over one year than has normally been observed in trials in the past. This may have contributed to a relatively large difference in cognitive decline between the placebo group and the high-dose group. If, in larger trials, the placebo group declines more slowly, it is not guaranteed the treatment groups will attain statistical significance for slowing down cognitive decline.
Third, there were some side effects, most notably brain swelling and headaches. “These side effects generally resolve on their own over time,” said Tanzi, “but they are a potential concern since they could lead to drop out of patients from future trials”. The side effects were most prevalent in the highest dose group and in carriers of the APOE4 risk gene (present in 60-70% of Alzheimer’s patients).
CAF has long supported the development of other anti-amyloid treatments, and is several years into a program developing a class of drugs called “gamma-secretase modulators” (GSM) that would also clear amyloid from the brain. While Biogen’s drug would have to be injected and will likely be very expensive, the GSM drug would be taken in a less costly and more convenient pill form. The GSM project, led by Tanzi and Steve Wagner, Ph.D, at the University of California at San Diego (UCSD), has been co-funded by CAF and the National Institutes of Health. The investigators hope to get the drug into Phase I trials later this year.
“This announcement also bodes well for our planned screen of ‘Alzheimer’s in a Dish’ aimed at finding more anti-amyloid (and anti-tangle) drugs,” said Tanzi. “We have our work cut out for us. But the prospects for our multi-track approach look better than ever thanks to impressive success of the new Biogen trial of aducanumab.”
Here is the New York Times article, which the above article is based on. While the headline seems to be even more misleading, the actual article is more critical of the results. It also discusses an important aspect of dementia research, which is the great amount of money in pharmaceutical research. While dementia research in general is grossly underfunded, there is a lot of money to be made in drugs! I haven’t actually been able to locate the original research article to read yet.
Biogen Reports Its Alzheimer’s Drug Sharply Slowed Cognitive Decline
An experimental drug for Alzheimer’s disease sharply slowed the decline in mental function in a small clinical trial, researchers reported Friday, reviving hopes for an approach to therapy that until now has experienced repeated failures.
The drug, being developed by Biogen Idec, could achieve sales of billions of dollars a year if the results from the small trial are replicated in larger trials that Biogen said it hoped to begin this year. Experts say that there are no really good drugs now to treat Alzheimer’s.
Biogen’s stock has risen about 50 percent since early December, when the company first announced that the drug had slowed cognitive decline in the trial, without saying by how much. Analysts and investors had been eagerly awaiting the detailed results, some of them flying to France to hear Biogen researchers present them at a neurology meeting on Friday.
The drug, called aducanumab, met and in some cases greatly exceeded Wall Street expectations in terms of how much the highest dose slowed cognitive decline. However, there was a high incidence of a particular side effect that might make it difficult to use the highest dose.
Still, the net impression was positive. “Out-of-the-ballpark efficacy, acceptable safety,” Ravi Mehrotra, an analyst at Credit Suisse, wrote on Friday. Shares of Biogen rose $42.33, or 10 percent, to $475.98.
Alzheimer’s specialists were impressed, but they cautioned that it was difficult to read much from a small early-stage, or Phase 1, trial that was designed to look at safety, not the effect on cognition. Also, other Alzheimer’s drugs that had looked promising in early studies ended up not working in larger trials.
“It’s certainly encouraging,” said Dr. Samuel Gandy, director of the Center for Cognitive Health at Mount Sinai Hospital in New York, who was not involved in the study. He said the effect of the highest dose was “pretty impressive.”
Aducanumab, which until now has been called BIIB037, is designed to get rid of amyloid plaque in the brain, which is widely believed to be a cause of the dementia in Alzheimer’s disease. However, other drugs designed to prevent or eliminate plaque have failed in large clinical trials, raising questions about what role the plaque really plays.
Johnson & Johnson and Pfizer abandoned a drug they were jointly developing after it showed virtually no effect in large trials. Eli Lilly and Roche are continuing to test their respective drugs despite initial failures. Experts say there is some suggestion the drugs might work if used early enough, when the disease is still mild.
Biogen tried to increase its chances of success by treating patients with either mild disease or so-called prodromal disease, an even earlier stage. It also enrolled only patients shown to have plaque in their brains using a new imaging technique. In some trials of other drugs, some of the patients turned out not to have plaque, which could have been a reason the trials were not successful.
The results reported Friday were for 166 patients, who were randomly assigned to get one of several doses of the drug or a placebo. The drug not only slowed cognitive decline but also substantially reduced plaque in the brain, and higher doses were better than lower doses. Those are signs that the effects seen were from the drug.
“It would be kind of hard to get those kind of results by chance,” said Dr. Rachelle S. Doody, director of the Alzheimer’s Disease and Memory Disorders Center at Baylor College of Medicine, who was not involved in the study but has been a consultant to Biogen and many other companies.
On one measure of cognition, a 30-point scale called the mini-mental state exam or M.M.S.E., those receiving the placebo worsened by an average of 3.14 points over the course of a year. The decline at one year was only 0.58 points for those getting the highest dose and 0.75 points for a middle dose. The difference with a placebo was statistically significant for both doses.
On another measure of both cognition and the ability to function in daily tasks, patients in the placebo group worsened by an average of 2.04 points at one year. Those getting the highest dose of the drug had a decline of only 0.59, a statistically significant difference.
Some analysts said they would have been impressed if the drug had slowed the rate of cognitive decline by 20 or 30 percent. But the actual reduction for the high dose was above 70 percent. They said the drug’s effect was stronger than that of Lilly’s drug.
A major side effect was a localized swelling in the brain, known as A.R.I.A.-E. This has been seen with other drugs in this class, though the rate for aducanumab seems higher.
Among patients with a genetic variant that raises the risk of getting Alzheimer’s, 55 percent of those who got the highest dose suffered this side effect, and about 35 percent of the high-dose patients dropped out of the trial because of this. Among those without the genetic variant, 17 percent of those who got the highest dose suffered the side effect and 8 percent discontinued treatment.
Biogen said the swelling often did not cause symptoms and probably could be managed by watching for it and reducing doses. Dr. Doody and Dr. Gandy agreed.
But Dr. Thomas M. Wisniewski, a professor of neurology at NYU Langone Medical Center, disagreed. “Most clinicians would find that unacceptable,” he said in a conference call hosted by the Wall Street firm Evercore ISI. He said the side effect was “something you definitely don’t want happening in your patients.”
Over all, however, Dr. Wisniewski was enthusiastic, saying the drug looked to be “way better” than Lilly’s.
A lesser dose might suffice. There were no discontinuations from this side effect among patients taking a middle dose. And that middle dose also seemed somewhat effective in slowing cognitive decline.
The results were presented in Nice, France, at the International Conference on Alzheimer’s and Parkinson’s Diseases and Related Neurological Disorders.