December 09, 2016

Three Strikes and You're Out

Three times, Eli Lilly has tried to demonstrate the efficacy of the drug solanezumab in the treatment of Alzheimer’s disease. And three times, the drug failed. What does this mean?

Solanezumab is a monoclonal antibody that selectively attaches to a form of amyloid-beta, widely thought to be the key agent that causes Alzheimer’s disease. The first two studies were phase three, double-blind studies of patients with mild to moderate Alzheimer’s disease. That means earlier studies had found the drug reasonably safe and had identified a dose that had the desired effect on brain amyloid. The results of EXPEDITION1  and EXPEDITION 2 were both published in the New England Journal of Medicine in January, 2014. The authors found that after 18 months of treatment with intravenous solanezumab, there was no improvement in either tests of cognitive function (the Alzheimer’s Disease Assessment Scale) or daily activities (the Alzheimer’s Disease Cooperative Study Activities of Daily Living scale). There was a hint in subgroup analysis that maybe the patients with milder disease might benefit; hence the new study, EXPEDITION3, which evaluated the drug in patients with clinical evidence of mild dementia and abnormalities on PET scan suggestive of amyloid deposition. But alas, the results of this trial are no more encouraging than those of its predecessors.

Solanezumab is not the only anti-amyloid monoclonal antibody that has been tested and found wanting. Two other double blind randomized, placebo-controlled phase 3 trials were conducted with Bapineuzumab in patients with mild to moderate Alzheimer’s, One trial involved carriers of the APOE-4 allele, a gene for a cholesterol carrying protein that has been associated with an increased risk of dementia; the other involved non-carriers. Once again, there was no difference between patients receiving active drug and those getting placebo, whether on tests of cognition or on measures of overall daily functioning.

So now solanezumab has failed three times. Not because it caused terrible side effects, as was the case with earlier attempts to “vaccinate” against Alzheimer’s disease, that were in some instances effective but that caused a debilitating and/or lethal inflammatory response in the central nervous system. Solanezumab failed because it didn’t work. What does this tell us about the use of monoclonal antibodies in Alzheimer’s disease?

An article in Scientific American two years ago on “Why Alzheimer’s Drugs Keep Failing” makes clear that it’s not just a handful of drugs that have fallen short of their promise. According to the article, “dementia has become a graveyard for a large number of promising drugs.” In fact, the failure rate for Alzheimer’s disease “drug candidates” is 99.6 percent (compared to 81 percent for cancer drugs). The problem, in large measure, is that symptoms begin a decade or more after the disease actually starts, by which time intervention may be too late. It’s as though we didn’t treat coronary artery disease until after a patient developed cardiomyopathy, until after so much heart muscle had died that the heart scarcely pumped at all. One strategy for drug development is therefore to identify markers for disease long before there are clinical manifestations, in principle allowing for treatment at a much earlier stage than occurred with any of the solanezumab trials. Another is to target other suspects besides amyloid—abnormal proteins such as tau that also contribute to the development of dementia. Still another strategy is to focus on “disease-modifying treatment,” an approach that slows the progression of the disease rather than one that focuses on cure.

Perhaps another reason that Alzheimer’s disease is such a hard nut to crack is that the brain is an extraordinarily complicated organ, arguably far more complex than the heart. The heart, after all, is basically a pump. An ingenious pump fed by a system of blood vessels and operated by an electrical mechanism, and one that has proved far more complicated than was initially assumed, but nonetheless simple by comparison with the brain. Because the brain is such a remarkable organ and because Alzheimer’s disease strikes its most elusive function, cognition, it is not entirely surprising that treating this disorder has proved so challenging.

The message is not that we should give up. But it is that there’s no cure around the corner. The most effective strategy to date is to decrease the likelihood of developing Alzheimer’s through a combination of smoking cessation, treatment of high blood pressure, and treatment (or prevention) of diabetes—a strategy developed for the prevention of cardiac disease and incidentally found to help stave off dementia. And in the mean time, as scientists continue to struggle to understand the pathogenesis of Alzheimer’s and devise new strategies for intervening in the relentless progression of this dread disease, we must continue to find better ways to support people who are afflicted, allowing them to find as much meaning and satisfaction as possible in their lives.

This is the last post on “Life in the End Zone” in 2016. See you next year!

December 05, 2016

Antipsychotics: Use as Directed

Antipsychotic medication is effective for people who are psychotic—period. It’s been used for other conditions, such as the behavioral symptoms of dementia, and it turned out not to work. It’s been used for delirium, a type of confusion that often arises in older people or people nearing the end of life, especially in the hospital, and many doctors swear it’s the only medication that helps this distressing and dangerous disorder. But a new study from Australia suggests that antipsychotic medication doesn’t work for delirium either. 

The specific situation the Australian doctors looked at was delirium in the setting of patients with advanced illness, either patients on an inpatient palliative care service or patients enrolled in a hospice facility. Out of well over 1000 patients with delirium, they were able to identify 247 who were both eligible and willing to enter the study. This group, with a mean age of 75, were randomized to risperidone (a commonly used antipsychotic), haloperidol (another commonly used antipsychotic), or placebo. Patients were also given unspecified non-medicinal treatment, presumably things like a sitter (someone to stay with them) or relaxation techniques such as massage. They were also given subcutaneous midazolam, a very short acting anti-anxiety medication under the skin, for extreme agitation. The results? Patients receiving either risperidone or haloperidol had more severe symptoms of delirium than those treated with placebo. They also, not surprisingly, had more Parkinsonian symptoms, the main side effect of these antipsychotic medications, and were more likely to die.

This is a disturbing result. Not only did antipsychotics fail to help, but they also seemed to make matters worse. Now maybe there’s something different about Australians, or maybe the specific environment they were in—a palliative care service or hospice, though neither is clearly described—makes generalization to the American general hospital impossible. Or maybe people with delirium and advanced illness are somehow different from people with delirium who don’t have an advanced illness. And conceivably, other antipsychotics such as quetiapine or olanzapine are different. More likely, antipsychotics are simply a bad choice in the treatment of delirium.

Antipsychotic medications are remarkable medications—for the treatment of psychosis in psychiatric conditions such as schizophrenia and bipolar disorder. But maybe we should stop using them for anything other than these indications.