IMPORTANCE Alzheimer disease (AD) is a neurodegenerative disorder characterized by cognitive deterioration and impaired activities of daily living. Current treatments provide only minor symptomatic improvements with limited benefit duration. Lanabecestat, a brain-permeable inhibitor of human beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1/β-secretase), was developed to modify the clinical course of AD by slowing disease progression. OBJECTIVE To assess whether lanabecestat slows the progression of AD compared with placebo in patients with early AD (mild cognitive impairment) and mild AD dementia.

Background We present findings from the multicenter, double-blind Phase 3 study, CENTURION. This study was designed to assess the efficacy of and consistency of response to lasmiditan in the acute treatment of migraine across four attacks. Methods Patients were randomized 1:1:1 to one of three treatment groups – lasmiditan 200 mg; lasmiditan 100 mg; or a control group that received placebo for three attacks and lasmiditan 50 mg for either the third or fourth attack. The primary endpoints were pain freedom at 2 h (first attack) and pain freedom at 2 h in ≥2/3 attacks. Secondary endpoints included pain relief, sustained pain freedom and disability freedom. Statistical testing used a logistic regression model and graphical methodology to control for multiplicity. Results Overall, 1471 patients treated ≥1 migraine attack with the study drug. Both primary endpoints were met for lasmiditan 100 mg and 200 mg ( p < 0.001). All gated secondary endpoints were met. The incidence of treatment-emergent adverse events (TEAEs) was highest during the first attack. The most common TEAEs with lasmiditan were dizziness, paresthesia, fatigue, and nausea; these were generally mild or moderate in severity. Conclusions These results confirm the early and sustained efficacy of lasmiditan 100 mg and 200 mg and demonstrate consistency of response across multiple attacks. Trial Registration Number: NCT03670810

Background Lasmiditan (LTN) is a selective 5-HT1F receptor agonist for the acute treatment of migraine in adults. We present detailed safety findings from the placebo-controlled, double-blind Phase 3 study, of LTN treatment across 4 attacks (CENTURION). Methods Patients were randomized 1:1:1 to LTN 200 mg (LTN200), LTN100, or a control group that received placebo for 3 attacks and LTN50 for either the 3rd or 4th attack (1:1). Safety analyses were conducted for patients who took ≥1 dose of study drug and, in some cases, those who took all 4 doses. Results Overall, 1471 patients treated 4494 attacks. The incidences of treatment-emergent serious adverse events (SAEs) were - placebo, n=2 (0.4 %); LTN100, n=1 (0.2 %); LTN200, n=2 (0.4 %); no specific treatment-emergent SAE was reported in more than one patient. The most common treatment emergent adverse events (TEAEs) with lasmiditan were dizziness, paresthesia, fatigue, nausea, vertigo, and somnolence; the vast majority were mild or moderate in severity. The incidences of these TEAEs were highest during the first attack and decreased during subsequent attacks. For patients who experienced a common TEAE with the first attack, less than 45 % experienced the same event in subsequent attacks. Patients who did not experience an event in the 1st attack infrequently experienced the same event in subsequent attacks. The time of onset of the common TEAE ranged from ~40 min to 1 h (dependent upon TEAE) and, for individual TEAE, the onset was similar across attacks. Duration was dependent upon TEAE and attack. It was shortest for paresthesia (< 2 h for all attacks); it ranged from 1.8 to 5.5 h for other common TEAEs and was generally similar across attacks. Serotonin syndrome was reported for 2 patients post LTN dosing; there were no meaningful differences across treatment groups in suicidality; there was no evidence of an increase in motor vehicle accidents. Conclusion In this blinded, controlled, multiple-attack study, LTN was associated with generally mild or moderate CNS-related TEAEs of short duration. TEAEs tended to decrease in frequency across the 4 attacks. Trial registration NCT03670810

Introduction: Lanabecestat, a beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) inhibitor, was investigated as a potential Alzheimer's disease (AD)-modifying treatment. As previously reported, amyloid beta (Aβ) neuritic plaque burden reduction did not result in clinical benefit. Lanabecestat's effects on neuroimaging biomarkers and correlations between neuroimaging biomarkers and efficacy measures are reported. Methods: AMARANTH and DAYBREAK-ALZ were 104-and 78-week, multicenter, randomized, double-blind, placebo-controlled studies of lanabecestat in early symptomatic AD (AMARANTH) and mild AD dementia (DAYBREAK-ALZ). Patients randomly (1:1:1) received placebo, lanabecestat 20 mg, or lanabecestat 50 mg daily (AMARANTH, n = 2218; DAYBREAK-ALZ, n = 1722). Florbetapir positron emission tomography (PET), fluorodeoxyglucose (FDG) PET, flortaucipir PET, and volumetric magnetic resonance imaging (MRI) were used to measure Aβ neuritic plaque burden, cerebral metabolism, aggregated tau neurofibrillary tangles, and brain volume, respectively. Additionally, florbetapir perfusion scans were performed in DAYBREAK-ALZ.

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