Eli Lilly halted two late-stage clinical trials of an experimental Alzheimer’s treatment on Tuesday, representing a setback to one leading theory on treating the degenerative disease and a new blow to Lilly’s business prospects.
One defining feature of Alzheimers disease is the presence of amyloid plaque in the brain . The now-halted clinical trial was for a drug which reduces this plaque.
The basic idea is fairly straightforward: if plaque is present in the brains of those with Alzheimer’s, removing the plaque may help reduce or reverse the symptoms. Instead, researchers were finding that the drug was making symptoms worse. Again from the times:
The company said patients who had taken the drug, intended to reduce plaque in the brain, actually showed worse cognitive functioning and less ability to perform daily living tasks than patients who had taken a placebo.
Why bring this up on an autism blog? Because this trial gives a good example of why I am very concerned about the use of untested therapies on autistics. It isn’t because of some objection to a “cure”. There is no existing autism cure. There is no autism cure proposed or in any stage of a clinical trial. While there is some very good and important discussions about any potential cure, it is for the present a hypothetical discussion. No, it isn’t the cure debate which drives me. It is safety. Plain and simple.
Consider autism therapies (both alternative and off-label) from a viewpoint of safety for the moment with the lessons learned from the Alzheimer’s trial.
Clinical trials are all about safety and efficacy. Is the therapy (drug) safe? Does it work? Before a clinical trial is even started, there has to be some reason to believe that the therapy would be safe and effective. Researchers have to ask the question, “what will this do?” In the Eli Lilly Alzheimer’s trial, they had reason to believe that the drug would reduce amyloid plaque. They had (I assume) some earlier trials to prove the drug reached some level of safety. With that in hand, Eli Lilly went forward to large-scale testing with people and they found that, at least for their test group (people with somewhat advanced Alzheimer’s disease), the drug was harmful.
From the NY Times story:
Lilly’s drug was intended to reduce production of so-called amyloid beta plaques in the brain by inhibiting the activity of an enzyme called gamma secretase.
Dr. Siemers of Lilly said the failed trials might indicate that too much reduction in amyloid beta unexpectedly harms cognitive functions, or it may be that the problems arose from the drug’s effect on some 20 other proteins.
Unintended and unforeseen consequences.
Consider alternative therapies being applied to autistics. For example, consider anti-inflammatory drugs. These are existing drugs used off-label, so some safety data are available. There is evidence of inflammation in the brains for some autistics, so why not treat it?
Because we don’t understand why there is inflammation in the brains of autistics. Because of that, we don’t know if there are any unintended consequences of anti-inflammatory therapies. From a story last year in the Chicago Tribune , this section discussing the team from Johns Hopkins/Kennedy Krieger which first published on neuroinflammation in autistics:
“THERE IS NO indication for using anti-inflammatory medications in patients with autism,” the [Johns Hopkins] team wrote.
Meddling with neuroinflammation could actually be a terrible mistake, said co-author Dr. Andrew Zimmerman, director of medical research at the Center for Autism and Related Disorders at the Kennedy Krieger Institute in Baltimore.
“It may actually be an attempt of the brain to repair itself,” said Zimmerman, a pediatric neurologist. Suppressing the immune response “could be doing harm.”
There are other classes of alternative therapies used in autism. Therapies which most likely are doing nothing beyond the placebo effect are in one class. For example, homeopathy. I don’t spend a lot of time writing about homeopathy. In fact, I don’t know if I have blogged about it at all. Even though it is bad science, it isn’t really dangerous. Another class of alternative therapies are those based in really bad science and which carry the potential of harm. Lupron comes readily to mind. Lupron therapy is based on two levels of very bad science. First, that autism is caused by mercury poisoning. Second, that reducing testosterone in the body will aid it in eliminating mercury. Lupron has been through clinical trials (not for autism) demostrating some level of safety, there are serious known side effects. Worse, the manner in which it is used in autistic children is very problematic—delaying puberty.
Back to the Alzheimer’s trial—I actually welcome the trial itself. I consider those who undertake clinical trials to be very brave individuals. I for one hope there are effective therapies for Alzheimer’s and other forms of dementia soon. It is a great fear for most, if not all, of us that we spend the last years of our lives with dementia. For the parent of a disabled child, this fear is only compounded. The thought of spending my last years draining resources I would rather leave to my child is one of the worst futures I can imagine.
Hi Sullivan -
For a fascinating discussion about this trial, check out this blog:
[See comment #24 for an especially intriguing idea, and indeed, a grand illustration for the possibilities of an unintended consequence]
This site, and especially the comments, provide a view into the pharma area that is quite refreshing, and oftentimes, borders on tragically sad.
In the Eli Lilly Alzheimer’s trial, they had reason to believe that the drug would reduce amyloid plaque.
Indeed. But we now would seem to have reason to think that the plague may not be the problem at all, but rather, the bodies attempt at a solution. Ooops.
They had (I assume) some earlier trials to prove the drug reached some level of safety.
Alzheimer's is a big problem for the drug industry; lots of money to be made, but possibly no way to get the right drug developed. There are those that think that effective treatments need to be started before signs of dementia become apparent, or at the latest, when the earliest signs of impairment are seen. But from those points on towards full blown dementia, or indeed, mortality, can be ten or more years. And if you spend tens (or hundreds?) of millions of dollars getting a drug through to phase III, then wait around for a decade before you find it doesn't help, then what? This is a kiss of death for an industry that lives and dies by the quarterly report.
Because we don’t understand why there is inflammation in the brains of autistics. Because of that, we don’t know if there are any unintended consequences of anti-inflammatory therapies.
As far as causation goes, might be making some progress there; at least in some cases. came out about a week ago and indicates that disturbances to the electron transport chain can differentially affect the immunological function of microglia such that immune regulatory components are downregulated.
In summary, we have shown that mitochondrial dysfunction in mouse microglial cells inhibit some aspects of alternative activation, whereas classic activation seems to
remain unchanged. If, in neurological diseases, microglial cells are also affected by mitochondrial dysfunction, they might not be able to induce a full anti-inflammatory alternative response and thereby exacerbate neuroinflammation. This would be associated with detrimental effects for the CNS since wound healing and attenuation of inflammation would be impaired.
Alternatively, animal models indicate that an immune insult during critical timeframes can ; similar to what was recently observed in Morgan et all. Morgan also speculated that some of their findings could be explained by an ongoing attempt to turn off an immune response.