Failed drugs for brain conditions

Animal models of human brain conditions generate useless drugs

MyelinRepair. 8 September 2010.
The Animal Issue
Posted by: Megan Rechin.


This is a flow chart that shows how to go from discovery biology to a clinical trial. The process of translational
research.

Time after time headlines in the news will spotlight a recently developed drug that may potentially provide treatment
to patients that suffer from diseases like Alzheimer’s, Parkinson’s and multiple sclerosis. These drugs appear in the
news because they have reached the late or near final stages of the drug development process where they can be tested in clinical trials involving humans who are living with these diseases. But again and again it seems that these drugs are discontinued at this late stage and are thwarted out of becoming the medical therapies their developers had hoped to create. Why is this so?

In a recent edition of The Lancet Neurology, an article discussed the problems for drug development in Alzheimer’s
disease. And, although the summary only focused on this disease, the problems discussed can explain why drugs being
tested for diseases like MS are also failing. One of the reasons that The Lancet Neurology gives to explain drug
failure is the animal issue. Before a drug can be tested in humans, it must go through an animal model that is designed to be as humanlike as possible.

This way researchers can observe how the drug will react with the newly developed treatment as if it were being tested in a human system. However, it is almost impossible to create an animal model that will react to a treatment in the same way a human would or one that can “accurately reflect human pathogenesis.” So, after experimentation, what a researcher has actually found is a drug that appears to  cure, alleviate symptoms of and repair damage from a disease in an animal.

Yet, when the drug is tested in humans and it does not have the same effect as it did in the animal model, the drug is
rendered useless to treat human diseases. Then it’s back to the drawing board. The term “translational research” is something else The Lancet Neurology questions. It looks easy on paper, but attempting to translate drug response in animal models to human clinical trials is something that rarely seems to pan out. This is why it is important to create animal models that directly model human pathogenesis.

If you would like to read more about this issue, check out the article in The Lancet Neurology here.

Failing drug trials for Alzheimer's

 

"...some animal models inaccurately predict drug efficacy. The failure of the translation of research could be attributable to poor methodology in animal studies, or the use of models that do not accurately reflect human pathogenesis. Another meta-analysis showed that neutral or non-significant animal studies are less likely to be published-such publication bias can overestimate efficacy."

 

 

The Lancet, Volume 376, Issue 9742, Page 658, 28 August 2010

Why are drug trials in Alzheimer's disease failing?

Last week, semagacestat added itself to the phase 3 scrapheap of other disease-modifying hopefuls for Alzheimer's disease. This drug is a γ-secretase inhibitor of the final step in amyloid-β protein synthesis, aggregates of which form plaques, the hallmark of the disease.

A recent review in The Lancet Neurology summarises the problems for drug development in Alzheimer's disease. Other drugs also failed phase 3 trials. Hopes were high for latrepirdine, but its CONNECTION study did not reveal a significant difference from control in March this year. Similarly, tramiprosate and tarenflurbil were abandoned.

These studies join trials for other neurological diseases, including stroke, multiple sclerosis, and Parkinson's disease, which, while showing promise in animal studies and early human trials, were discontinued at late stages. How do these drugs manage to progress to this stage?

Meta-analysis suggested that some animal models inaccurately predict drug efficacy. The failure of the translation of research could be attributable to poor methodology in animal studies, or the use of models that do not accurately reflect human pathogenesis. Another meta-analysis showed that neutral or non-significant animal studies are less likely to be published-such publication bias can overestimate efficacy.

Current treatment targets patients with symptomatic Alzheimer's disease. But perhaps the disease is being treated too late, when damage is irreparable? The best time to treat Alzheimer's disease is likely to be before memory loss and tissue destruction occurs, but this is hard to model in animals. That means identifying people at risk of developing the disease, perhaps because of a genetic predisposition or by measuring biomarkers, such as the recently reported cerebrospinal fluid measurement of a mix of amyloid β1-42 and phosphorylated τ protein.

Drug-industry scientists are failing themselves if their animal studies are poorly done or use the wrong model, and their companies are failing academics who do their phase 3 trials with them, trial participants, and shareholders. Perhaps the problem is "translational research" itself: a phrase much bandied around, but does anyone know what it really means, let alone how to do it?

For the meta-analyses see PLoS Med 2010; 7: e1000245 and PLoS Biol 2010; 8: e1000344

For the biomarker study see Arch Neurol 2010; 67: 949-56