Alzheimer Disease (AD) is the most prevalent cause of dementia, characterized by initial memory impairment and progressive cognitive decline. The exact cause of AD is not yet completely understood. However, the presence of neurotoxic amyloid-beta (Aβ) peptides in the brain is often cited as the main causative agent in AD pathogenesis. In accordance with the amyloid hypothesis, Aβ accumulation initially occurs 15-20 years prior to the development of clinical symptoms. Current therapies focus on the prodromal and preclinical stages of AD due to past treatment failures involving patients with mild to moderate AD. Passive immunization via exogenous monoclonal antibodies (mAbs) administration has emerged as a promising anti-Aβ treatment in AD. This is reinforced by the recent approval of the mAb, aducanumab. mAbs have differential selectivity in their epitopes, each recognising different conformations of Aβ. In this way, various Aβ accumulative species can be targeted. mAbs directed against Aβ oligomers, the most neurotoxic species, are producing encouraging clinical results. Through understanding the process by which mAbs target the amyloid cascade, therapeutics could be developed to clear Aβ, prevent its aggregation, or reduce its production. This review examines the clinical efficacy evidence from previous clinical trials with anti-Aβ therapeutics, in particular, the mAbs. Future therapies are expected to involve a combined-targeted approach to the multiple mechanisms of the amyloid cascade in a particular stage or disease phenotype. Additional studies of presymptomatic AD will likely join ongoing prevention trials, in which mAbs will continue to serve as the focal point.
Functional activation of the PI3K/AKT/mTOR pathway is seen in ~50% of low-grade gliomas and correlates with worse survival. Everolimus is a selective inhibitor of mTOR that targets mTOR-raptor signaling, halting proliferation and indirectly inhibiting angiogenesis. This phase 2 study evaluated the efficacy of everolimus in untreated grade II diffuse glioma. Patients were stratified by 1p19q status and PI3K pathway activation (via phosphorylation of PRAS-40) into three arms: 1) 1p19q intact, PRAS-40 phosphorylated received everolimus monotherapy; 2) 1p19q intact, PRAS-40 not phosphorylated received everolimus with temozolomide; and 3) 1p19q co-deleted received everolimus monotherapy. Primary outcome was landmark PFS-33 months for Arms 1 and 2; and PFS-38 months for Arm 3 (null hypothesis 50% for all arms individually). Key eligibility criteria included central pathology confirmation, no prior treatment, and initiation of everolimus within 120 days of most recent tissue sampling. From 05/2014 to 07/2018, 27 patients were enrolled – 16 into Arm 1; 2 into Arm 2; and 9 into Arm 3. Median age at enrollment was 38 years (range 21 – 65); median KPS 90 (range 70 – 100) and a majority were male (74%). Although follow-up is not complete, as of 05/2019 11 of 16 patients had progressed prior to 33 months in Arm 1, and 5 of 9 patients had progressed prior to 38 months in Arm 3. Toxicity was as expected with frequent grade 1/2 AEs of diarrhea, rash, and mucositis. Headache was the most common grade 3 AE and was seen in three cases. The study was closed prematurely secondary to slow accrual and loss of drug support. Updated survival data as well as results of secondary and exploratory analyses will be reported. In summary, everolimus was well tolerated in previously untreated low-grade gliomas. However, it failed to meet primary outcome of extending PFS in this population.
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