It is not unusual to read about another drug failure in a challenging neurological disease such as multiple sclerosis, Alzheimer’s disease, or Parkinson’s disease. Designing therapeutics with exquisite specificity has been the goal of modern drug development, and significant resources continue to be allocated towards this approach, only to see treatments fail due to inadequate efficacy or intolerable side effects. How we approach the development of new therapeutics for treating complex diseases will be key for achieving better patient outcomes.
A recent example of a once promising drug candidate using a targeted approach is semagacestat, a treatment developed by Eli Lilly and Elan. Proposed to lower the build-up of harmful plaques in the brain of Alzheimer’s disease patients, its Phase III trial was halted last August because semagacestat worsened clinical symptoms compared to placebo. Semagacestat targets a single enzyme called gamma secretase, which turns a protein found in normal brain into amyloid, the building block of the plaques found in Alzheimer’s disease. Semagacestat’s failure represents the difficulties in developing treatments that target specific molecules, whether these targets are surface proteins or signaling pathway intermediates inside of cells.
Several stumbling blocks can be identified in the development of targeted therapies, using semagacestat as an example:
1. The role of the target is not well established.
Many drugs target proteins whose function within a specific disease is difficult to ascertain. Alzheimer’s disease is characterized by the presence of plaques that prevent nerve cells from communicating. The therapeutic value of targeting plaque build-up is unclear, and a lack of definition for the exact role of amyloid in disease progression adds uncertainty for the therapeutic effectiveness of drugs like semagacestat.
2. Redundancy in cellular communication prevents efficacy of the drug in the absence of toxicity
Obstructing the generation of amyloid alone has limited effect on the complex nature of Alzheimer’s disease. The dysregulation of a group of proteins called Tau has recently taken the forefront as another important contributor. Genetic factors, such as variations in the lipoprotein APOE, play a significant role in disease progression and may greatly impact the ability of proposed therapeutics to affect the entire patient population. In addition, inflammation
