TPI 287 is a tubulin-binding and microtubule-stabilizing drug in Phase I trials in patients with mild-to-moderate AD, which is set to run until 2017.1). Tau stabilizers fail to reach the clinic, due to toxic side effects or have been discontinued for AD, or are in Phase I clinical development for mild-to-moderate AD. Prevention of tau aggregation by tau aggregation inhibitors Prevention of aggregation regardless of phosphorylation or other tau modification is another therapeutic approach.
Derivatives of methylene blue have been shown to disrupt the aggregation of tau, such as Rember™, which showed some improvement in AD-related symptoms but failed in Phase II because of emergent side effects including diarrhea, urinary urgency, painful urination, dizziness, and falls [59, 60].1). TRx0237 is a second-generation tau protein aggregation inhibitor currently in three Phase III trials.
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The second Phase III trial, in patients with mild-to-moderate AD, produced negative results ; the third trial in behavioral variant frontotemporal dementia failed to achieve its co-primary endpoints.
Enhancement of phosphorylated-tau clearance by active immunotherapy High-affinity antibodies against phosphorylated-tau from active immunization of phosphorylated-tau is one approach, such as AADvac-1, which contains synthetic tau294-305 peptides, and also ACI-35, which contains phosphorylated S396 and S404 tau fragments; AADvac-1 is in Phase II trials and ACI-35 is in Phase I trials.
The vaccine has undergone a Phase I trial in patients with mild-to-moderate AD, which is now in follow-up and is considering advancement to Phase II trials.
The rationale for IVIG in AD treatment is that IVIG can direct against Aβ. Although IVIG shows safe, well tolerated, anti-amyloid and immune modulatory properties in patients with AD, later Phase III trials indicate that IVIG exerts effects on cognition or function in patients with mild-to-moderate AD. Nasal insulin Insulin is a hormone for Type 1 diabetes treatment, the rationale for AD treatment is that brain areas affected in AD patients show decrease in the concentration of insulin and increase in the number of insulin receptors.
Over two hundred compounds have reached Phase II clinical trials since 2003, but no new drugs have been approved for the treatment of AD [4, 10]. Most Phase II clinical trials ending with a positive outcome do not succeed in Phase III, often due to serious adverse effects or lack of therapeutic efficacy.