![]() Disease modifying and/or proven function in the pathophysiology Highly selective to reduce adverse events However, Gandy noted that even though there is much interest in oligomeric β-amyloid because some experts believe it may be the toxin associated with many degenerative diseases, it is not a well-established drug target, and there are currently limited biomarkers for this peptide ( Reitz, 2012). Gandy noted that β-amyloid 42 fulfills most of the criteria, with three exceptions: (1) there is ambiguous evidence regarding proven function in pathophysiology of diseases (2) it is uniformly distributed throughout the body, which can lead to peripheral side effects when modulated and (3) a biomarker for monitoring therapeutic efficacy or target modulation is not entirely perfected. Gandy evaluated β-amyloid 42 and oligomeric β-amyloid against a list of criteria for an ideal drug target to determine whether or not they were strong targets for therapeutic development (see Box 4-1). 2 In the case of AD, the accumulation of β-amyloid 42 or its assembly form, oligomeric β-amyloid, begins as early as 15 years prior to symptoms ( Rowe et al., 2010). ![]() One pathological feature shared by these conditions is abnormal extracellular deposits of β-amyloid 42. Gandy discussed how early validation of targets can accelerate therapeutic development using examples from Alzheimer’s disease (AD) and traumatic encephalopathy 1 (acute and chronic). In addition, Kalpana Merchant, chief scientific officer of Tailored Therapeutics–Neuroscience at Eli Lilly and Company, offered a portfolio assessment tool outlining specific metrics for target validation and qualification, which could help assess confidence in a drug throughout the development process. ![]() Early validation of targets along with improved biomarkers were two opportunities discussed by Samuel Gandy, professor in the departments of neurology and psychiatry and associate director of Mount Sinai’s Alzheimer’s Disease Research Center, and Reisa Sperling, director of the Center for Alzheimer’s Research and Treatment and professor of neurology at Harvard Medical School. If a target cannot be validated, then it will not proceed in the drug development process. Target validation ensures that engagement of the target has potential therapeutic benefit like target identification, this is a critical step in drug development. This list is not meant to reflect a consensus among workshop participants. NOTE: The items in this list were addressed by individual speakers and participants and were identified and summarized for this report by the rapporteurs, not the workshop participants. Going directly into first-in-human trials might be feasible for highly validated targets.
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