Why are drug trials in Alzheimer's disease failing?

Abstract

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: e1000344For the biomarker study see Arch Neurol 2010; 67: 949–56 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: e1000344For the biomarker study see Arch Neurol 2010; 67: 949–56 For the meta-analyses see PLoS Med 2010; 7: e1000245 and PLoS Biol 2010; 8: e1000344For the biomarker study see Arch Neurol 2010; 67: 949–56 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