The A4 Study was a 240-week, double-blind, placebo-controlled Phase 3 secondary prevention trial in cognitively unimpaired adults (ages 65-85) with elevated amyloid on PET testing solanezumab, a monoclonal antibody targeting soluble amyloid-beta. The companion LEARN Study enrolled participants who were otherwise eligible for A4 but did not show elevated amyloid. Entry criteria included CDR-Global Scale (CDR-GS) = 0, MMSE≥25, WMS Logical Memory = 6-18, and elevated amyloid on florbetapir PET (for A4). The primary outcome measure was the Preclinical Alzheimer Cognitive Composite (PACC) with key secondary functional measures: Cognitive Function Index (CFI), Activities of Daily Living Scale (ADL), and CDR-GS. A subset of participants underwent flortaucipir Tau PET. For A4, 1169 randomized: 578 to solanezumab and 591 to placebo. Treatment groups were well matched. Solanezumab did not slow cognitive decline on the PACC (mean change (95% CI): placebo -1.13 (-1.45,-0.81); solanezumab -1.43 (-1.83,-1.03); p = .260). Secondary clinical outcomes were consistent, numerically favoring placebo. Across both arms, 36.1% progressed to symptomatic AD, defined as CDR-GS> 0 at two consecutive visits or final visit. Higher baseline amyloid levels were strongly associated with faster cognitive decline and greater risk of progression to symptomatic AD across both groups (p<.001). Amyloid continued to accumulate in both placebo (65.9 centiloid baseline, 19.3 increase) and solanezumab (66.2 centiloid baseline, 11.6 increase) groups. Tau PET showed similar increases in placebo and solanezumab groups in medial temporal lobe and neocortical composites, that were negatively correlated with PACC decline. No serious safety signals for solanezumab were identified, with only one case of ARIA-E. ARIA-H rates were similar across groups. LEARN participants (N = 538, 4.2 centiloid baseline on amyloid PET) did not demonstrate cognitive decline. The A4 Study demonstrated the feasibility of conducting a large-scale trial in preclinical AD, with cognitive and functional measures sensitive to decline. Solanezumab did not slow cognitive decline or clinical progression. Baseline amyloid PET was among the strongest predictors of decline across both placebo and solanezumab. LEARN participants did not demonstrate decline. These results suggest that amyloid plaque removal may be necessary even at this very early stage of AD.

In TRAILBLAZER-ALZ, amyloid clearance (defined as reaching <24.1 centiloids, CL) (Navitsky, 2018) was achieved for 40% of participants (mean baseline 107.6 CL) after 6 months of donanemab treatment (Mintun, 2021). The estimated time course of natural amyloid plaque accumulation at the amyloid-negative stage is approximately 3.3 CL/year (Jagust, 2021). Our objective was to examine the longer-term effect of donanemab on brain amyloid deposition by evaluating the amyloid re-accumulation observed in trial participants who reached clearance and were no longer receiving donanemab infusions, and compare it with amyloid accumulation for untreated amyloid-negative participants. In I5T-MC-AACD (NCT02624778) and TRAILBLAZER-ALZ (NCT03367403), we identified N = 46 participants with ≥2 post-treatment florbetapir scans conducted approximately 6 months after reaching amyloid clearance (Table 1). Part C of ongoing TRAILBLAZER-EXT trial (NCT04640077) is evaluating participants from TRAILBLAZER-ALZ at least 52 weeks after the participant’s last dose of donanemab. To examine re-accumulation rate, a linear regression was used to analyze change in amyloid level during post-treatment using follow-up time (in years) as a covariate. Furthermore, an advanced exposure-response model (ERM) with all available dosing, pharmacokinetic and florbetapir data, over treatment and post-treatment periods was employed (N = 304). Among 46 participants who achieved amyloid clearance after donanemab treatment, a single participant (∼2%) became amyloid-positive. The average amyloid level (mean±SD) changed from 4.4±8.9 to 3.9±11.4 CL during the observation period (mean 9.7±3.1 months) after stopping dosing. The rate of annualized change in amyloid level is approximately 3.4 CL/year. The rate of change in amyloid level was not significantly associated with amount of amyloid reduced over the treatment period or amyloid level achieved post-treatment. ERM predicted an average rate of 3.4 CL/year for amyloid re-accumulation in patients who reached clearance. The post-treatment florbetapir scans at 9.7±3.1 months for amyloid-negative I5T-MC-AACD and TRAILBLAZER-ALZ participants suggest that a re-accumulation rate is comparable with the inherent amyloid accumulation rate. Additional analyses of TRAILBLAZER-EXT data with the longer post-treatment period will be presented at the conference. Treatment with donanemab not only reduces amyloid levels in early, symptomatic AD patients below the amyloid-positive threshold but also places them on a plaque accumulation trajectory similar to untreated, amyloid-negative patients.

BACKGROUND:Trials of monoclonal antibodies that target various forms of amyloid at different stages of Alzheimer's disease have had mixed results. METHODS:We tested solanezumab, which targets monomeric amyloid, in a phase 3 trial involving persons with preclinical Alzheimer's disease. Persons 65 to 85 years of age with a global Clinical Dementia Rating score of 0 (range, 0 to 3, with 0 indicating no cognitive impairment and 3 severe dementia), a score on the Mini-Mental State Examination of 25 or more (range, 0 to 30, with lower scores indicating poorer cognition), and elevated brain amyloid levels on 18F-florbetapir positron-emission tomography (PET) were enrolled. Participants were randomly assigned in a 1:1 ratio to receive solanezumab at a dose of up to 1600 mg intravenously every 4 weeks or placebo. The primary end point was the change in the Preclinical Alzheimer Cognitive Composite (PACC) score (calculated as the sum of four z scores, with higher scores indicating better cognitive performance) over a period of 240 weeks. RESULTS:A total of 1169 persons underwent randomization: 578 were assigned to the solanezumab group and 591 to the placebo group. The mean age of the participants was 72 years, approximately 60% were women, and 75% had a family history of dementia. At 240 weeks, the mean change in PACC score was -1.43 in the solanezumab group and -1.13 in the placebo group (difference, -0.30; 95% confidence interval, -0.82 to 0.22; P = 0.26). Amyloid levels on brain PET increased by a mean of 11.6 centiloids in the solanezumab group and 19.3 centiloids in the placebo group. Amyloid-related imaging abnormalities (ARIA) with edema occurred in less than 1% of the participants in each group. ARIA with microhemorrhage or hemosiderosis occurred in 29.2% of the participants in the solanezumab group and 32.8% of those in the placebo group. CONCLUSIONS:Solanezumab, which targets monomeric amyloid in persons with elevated brain amyloid levels, did not slow cognitive decline as compared with placebo over a period of 240 weeks in persons with preclinical Alzheimer's disease. (Funded by the National Institute on Aging and others; A4 ClinicalTrials.gov number, NCT02008357.).

Solanezumab is a monoclonal antibody that preferentially binds soluble amyloid beta and promotes its clearance from the brain. The aim of this post hoc analysis was to assess the effect of low-dose solanezumab (400 mg) on global brain volume measures in patients with mild or moderate Alzheimer's disease (AD) dementia quantified using volumetric magnetic resonance imaging (vMRI) data from the EXPEDITION clinical trial program. Patients with mild or moderate AD (EXPEDITION and EXPEDITION2) and mild AD (EXPEDITION3), were treated with either placebo or solanezumab (400 mg) every 4 weeks (Q4W) for 76 weeks. vMRI scans were acquired at baseline and at 80 weeks from 427 MRI facilities using a standardized imaging protocol. Whole brain volume (WBV) and ventricle volume (VV) changes were estimated at 80 weeks using either boundary shift integral (EXPEDITION and EXPEDITION2) or tensor-based morphometry (EXPEDITION3). The pooled cohort used for this study consisted of participants with vMRI at baseline and week 80 across the three trials. Analyzed patient subgroups comprised full patient cohort ( N = 2933), apolipoprotein E ( APOE ) ε4 + carriers ( N = 1835), and patients with mild ( N = 2497) or moderate AD dementia ( N = 428). No significant effect (all P -values ≥.05) of treatment was observed in the pooled sample, individual trials, or subgroups of patients with mild or moderate AD or APOE ε4 carriers, in either WBV or VV change. Analysis of patients with mild or moderate AD dementia from baseline to 80 weeks using vMRI measures of WBV and VV changes suggested that low-dose solanezumab was not linked to changes in volumes at 80 weeks. Analysis of the pooled cohort did not demonstrate an effect on brain volumes with treatment. Evaluation of a higher dose of solanezumab in the preclinical stage of AD is currently being undertaken.

The metabolites of tryptophan-kynurenines with convulsant action quinolinic acid (QA) and l-kynurenine (l-KYN) antagonized the enhancing effect of pentobarbital (1 mM) on [3H]Flunitrazepam binding. IC50 for l-KYN were 35.9 +/- 14.8 microM and for QA 31.2 +/- 7.2 microM respectively. The inhibitory effect of KYN was stereoselective: IC50 of l-isomer was about two fold lower than IC50 of racemic form, d,l-KYN. Scatchard analysis revealed that inhibitory effect of QA and l-KYN on [3H]Flunitrazepam binding enhanced by pentobarbital is due to the decrease in affinity of benzodiazepine receptors. On the basis of these data it is proposed that QA and l-KYN possess their convulsant action interacting with barbiturate/picrotoxin sensitive sites of GABA-benzodiazepine-barbiturate complex.

Letter to the Editor Pain Freedom at 2 to 8 Hours With Lasmiditan: A Comparison With Rimegepant and Ubrogepant Erin G. Doty MD, Corresponding Author Erin G. Doty MD doty_erin_gautier@lilly.com Eli Lilly and Company, Indianapolis, IN, USASearch for more papers by this authorJohn H. Krege MD, John H. Krege MD Eli Lilly and Company, Indianapolis, IN, USASearch for more papers by this authorGerhardt Pohl PhD, Gerhardt Pohl PhD Eli Lilly and Company, Indianapolis, IN, USASearch for more papers by this authorMichael Case PhD, Michael Case PhD Eli Lilly and Company, Indianapolis, IN, USASearch for more papers by this authorSherie A. Dowsett PhD, Sherie A. Dowsett PhD Eli Lilly and Company, Indianapolis, IN, USASearch for more papers by this authorStewart J. Tepper MD, Stewart J. Tepper MD Geisel School of Medicine at Dartmouth, Hanover, NH, USASearch for more papers by this author Erin G. Doty MD, Corresponding Author Erin G. Doty MD doty_erin_gautier@lilly.com Eli Lilly and Company, Indianapolis, IN, USASearch for more papers by this authorJohn H. Krege MD, John H. Krege MD Eli Lilly and Company, Indianapolis, IN, USASearch for more papers by this authorGerhardt Pohl PhD, Gerhardt Pohl PhD Eli Lilly and Company, Indianapolis, IN, USASearch for more papers by this authorMichael Case PhD, Michael Case PhD Eli Lilly and Company, Indianapolis, IN, USASearch for more papers by this authorSherie A. Dowsett PhD, Sherie A. Dowsett PhD Eli Lilly and Company, Indianapolis, IN, USASearch for more papers by this authorStewart J. Tepper MD, Stewart J. Tepper MD Geisel School of Medicine at Dartmouth, Hanover, NH, USASearch for more papers by this author First published: 22 July 2020 https://doi.org/10.1111/head.13899Citations: 6 Conflicts of Interest: EGD, JHK, GP, MC, SAD – full-time employees and minor stockholders, Eli Lilly and Company. ST – Grants for research (no personal compensation): Alder, Allergan, Amgen, Dr. Reddy's, ElectroCore, Eli Lilly and Company, eNeura, Neurolief, Novartis, Scion Neurostim, Teva, Zosano. Consultant and/or Advisory Boards (honoraria): Acorda, Alder, Alexsa, Align Strategies, Allergan, AlphaSights, Amgen, Aperture Venture Partners, Aralez Pharmaceuticals Canada, Axsome Therapeutics, Becker Pharmaceutical Consulting, BioDelivery Sciences International, Biohaven, Charleston Labs, Decision Resources, DeepBench, ElectroCore, Eli Lilly and Company, eNeura, Equinox, ExpertConnect, GLG, GSK, Guidepoint Global, Healthcare Consultancy Group, Health Science Communications, Impel, Lundbeck, M3 Global Research, Magellan Rx Management, Marcia Berenson Connected Research and Consulting, Medicxi, Navigant Consulting, Neurolief, Nordic BioTech, Novartis, Pfizer, Pulmatrix, Reckner Healthcare, Relevale, Revance, SAI MedPartners, Satsuma, Scion Neurostim, Slingshot Insights, Sorrento, Spherix Global Insights, Sudler and Hennessey, Synapse Medical Communications, Teva, Theranica, Thought Leader Select, Trinity Partners, XOC, Zosano. Salary: Dartmouth-Hitchcock Medical Center, American Headache Society. Stock options: Nocira, Percept. CME honoraria: American Academy of Neurology, American Headache Society, Cleveland Clinic Foundation, Diamond Headache Clinic, Elsevier, Forefront Collaborative, Hamilton General Hospital, Ontario, Canada, Headache Cooperative of New England, Henry Ford Hospital, Detroit, Inova, Medical Learning Institute PeerView, Miller Medical Communications, North American Center for CME, Physicians' Education Resource, Rockpointe, WebMD/Medscape Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume60, Issue8September 2020Pages 1793-1796 RelatedInformation

GLADIATOR was a prospective, randomized, open-label, phase 3 study of lasmiditan 100 mg or 200 mg dosed intermittently for up to 1 year in patients with episodic migraine. Most patients had completed one of two single-attack studies before participation. A total of 2030 patients received ≥1 lasmiditan dose and 19,879 migraine attacks were treated. Safety results were similar to the previously reported interim analysis. The most frequently reported treatment-emergent adverse events (TEAEs) included dizziness (18.5%), somnolence (8.5%), and paresthesia (6.8%), with frequency of adverse events appearing to decrease with subsequently treated attacks. At 2 h post-dose, 26.7% and 32.2% of all attacks treated with lasmiditan 100 mg and 200 mg, respectively, were pain free. This pattern was generally consistent across study quarters and treated attacks. In conclusion, during a 1-year treatment period, intermittent lasmiditan for episodic migraine treatment was associated with generally decreasing TEAEs and consistent efficacy.

Lasmiditan (LY573144/COL-144) is a high-affinity, centrally penetrant, selective 5-HT 1F receptor agonist currently under investigation for acute treatment of migraine. Although lasmiditan is not known to induce vasoconstriction, it remains important to understand its effect on cardiovascular parameters because it is likely to be coadministered with β-adrenergic receptor antagonists used for migraine prophylaxis, such as propranolol. This phase 1, single-center, open-label, fixed-sequence study evaluated the cardiovascular and pharmacokinetic effects of 200 mg lasmiditan in 44 healthy subjects receiving repeated oral doses of twice-daily 80 mg propranolol under fasting conditions. Coadministration caused statistically significant decreases in mean hourly heart rate relative to propranolol alone, but the maximum magnitude of this effect was –6.5 bpm and recovered to predose levels by 3 to 4 hours before stabilizing. Additionally, short-lived (≤2.5 hours) statistically significant increases in systolic blood pressure (8.3 mm Hg) and diastolic blood pressure (6.4 mm Hg) were observed following coadministration. Consistent with the largely nonoverlapping metabolic pathways of lasmiditan and propranolol, exposure to either drug was not affected by coadministration. Overall, compared with administration of either drug alone, coadministration was generally well tolerated.

May 5, 2019April 9, 2019Free AccessLong-term Safety and Efficacy of Lasmiditan for Acute Treatment of Migraine Over a One-Year Period: Interim Results of an Open-Label Phase 3 Study (GLADIATOR) (P1.10-021)Jan Brandes, David Kudrow, Suzanne Klise, John H. Krege, Michael Case, Joel Raskin, Rashna Khanna, and Raghavendra VasudevaAuthors Info & AffiliationsApril 9, 2019 issue92 (15_supplement)https://doi.org/10.1212/WNL.92.15_supplement.P1.10-021 Letters to the Editor

Lasmiditan, a serotonin 5-HT1F receptor agonist, was effective for acute treatment of patients with migraine in a phase 3 double-blind randomized controlled study. The current study was designed to replicate these findings in a generalizable population of patients with migraine, including those with a cardiovascular medical history. This prospective, double-blind, phase 3 multicentre study randomly assigned patients with migraine with and without aura (1:1:1:1 ratio) to oral lasmiditan 200 mg, 100 mg, 50 mg, or placebo. Patients were instructed to dose at home within 4 h of onset of migraine attack of at least moderate intensity and not improving. The primary objective was to assess the proportion of patients' headache pain-free and most bothersome symptom-free at 2 h post-dose for each dose of lasmiditan versus placebo (NCT02605174). Patients (n = 3005) were assigned and treated (n = 2583, safety population): 1938 lasmiditan (200 mg n = 528, 100 mg n = 532, and 50 mg n = 556 included in primary analysis) and 645 placebo (540 included in primary analysis). Most patients (79.2%) had ≥1 cardiovascular risk factor at baseline, in addition to migraine. Lasmiditan was associated with significantly more pain freedom at 2 h (lasmiditan 200 mg: 38.8%, odds ratio 2.3, 95% confidence interval 1.8-3.1, P < 0.001; 100 mg: 31.4%, odds ratio 1.7, 1.3-2.2, P < 0.001; 50 mg: 28.6%, odds ratio 1.5, 1.1-1.9, P = 0.003 versus placebo 21.3%) and freedom from most bothersome symptom at 2 h (lasmiditan 200 mg: 48.7%, odds ratio 1.9, 95% confidence interval 1.4-2.4, P < 0.001; 100 mg: 44.2%, odds ratio 1.6, 1.2-2.0, P < 0.001; 50 mg: 40.8%, odds ratio 1.4, 1.1-1.8, P = 0.009 versus placebo 33.5%). Treatment-emergent adverse events were reported in 253 of 649 (39.0%), 229 of 635 (36.1%), and 166 of 654 (25.4%) of patients on lasmiditan 200, 100, and 50 mg, respectively, versus 75 of 645 (11.6%) on placebo. Most adverse events were CNS-related and included dizziness, somnolence and paraesthesia. Lasmiditan was effective at 2 h post-dose for acute treatment of migraine at all oral doses tested. Efficacy and safety were consistent with the previous phase 3 study.

Abstract Introduction Solanezumab is a humanized monoclonal antibody that preferentially binds to soluble amyloid β and promotes its clearance from the brain in preclinical studies. The objective of this study was to assess the effect of solanezumab in slowing global and anatomically localized brain atrophy as measured by volumetric magnetic resonance imaging (MRI). Methods In the EXPEDITION3 phase 3 trial, participants with mild Alzheimer's disease were randomized to receive intravenous infusions of either 400 mg of solanezumab or placebo every 4 weeks for 76 weeks. Volumetric MRI scans were acquired at baseline and at 80 weeks from 275 MRI facilities using a standardized imaging protocol. A subset of 1462 patients who completed both MRI and 14‐item Alzheimer's Disease Assessment Scale–Cognitive Subscale assessments at both time points were selected for analysis. Longitudinal MRI volume changes were analyzed centrally by tensor‐based morphometry with a standard FreeSurfer brain parcellation. Prespecified volumetric measures, including whole brain and ventricles, along with anatomically localized regions in the temporal, parietal, and frontal lobes were evaluated in those participants. Results Group‐mean differences in brain atrophy rates were directionally consistent across a number of brain regions but small in magnitude (1.3–6.9% slowing) and not statistically significant when corrected for multiple comparisons. The annualized rates of change of the volumetric measures and the correlation of these changes with cognitive changes in placebo‐treated subjects were similar to those reported previously. Discussion In the EXPEDITION3 trial, solanezumab did not significantly slow down rates of global or anatomically localized brain atrophy. Brain volume changes and their relationship to cognition were consistent with previous reports.

Objectives To address the need for long-term lasmiditan data, the GLADIATOR study evaluated the safety (primary) and efficacy (secondary) of lasmiditan for the intermittent, acute treatment of migraine attacks for up to 1 year. Methods In this prospective, randomized, open-label, Phase 3 study, patients who had completed either of two single-attack studies were offered the opportunity to be randomized 1:1 to lasmiditan 100 mg or 200 mg. Patients were asked to use lasmiditan as the first treatment for each new migraine attack of at least moderate severity. Assessments occurred at baseline and at prespecified time increments up to 48 hours after each dose of study drug using an electronic diary, and safety was assessed throughout the study. Migraine Disability Assessment (MIDAS) was assessed at each visit. Results As of the cut-off date for this interim analysis (6 March 2018), 1978 patients had received >= 1 lasmiditan dose and treated 19,058 migraine attacks. Overall, treatment-emergent adverse events (TEAEs) were similar to those in the single-attack studies and included dizziness (18.6%), somnolence (8.5%), and paresthesia (6.8%). The frequency of TEAEs generally decreased with subsequent attacks. No treatment-related serious adverse events and no cardiovascular TEAEs potentially due to vasoconstriction were observed. For both lasmiditan doses, efficacy measures were generally consistent over study quarters and treated attacks. Overall, across all treated attacks at 2 hours post-dose, pain freedom was observed in 26.9% of the attacks treated with lasmiditan 100 mg and 32.4% of the attacks treated with lasmiditan 200 mg. MIDAS total scores decreased over time. Conclusions The interim results of this long-term study showed intermittent lasmiditan (100 mg and 200 mg) to be generally well tolerated and efficacious for the acute treatment of migraine over a 1-year period.

BackgroundWe studied the efficacy and safety of a second dose of lasmiditan for acute treatment of migraine.MethodsSAMURAI and SPARTAN were double-blind, placebo-controlled Phase 3 studies in which individuals with migraine were randomized to oral lasmiditan 50mg (SPARTAN only), 100mg, 200mg, or placebo. Study drug was to be taken within 4 hours (h) of onset of a migraine attack (moderate or severe pain). A second dose of study drug was provided for rescue (patient not pain-free at 2h and took a second dose 2-24h post-first dose) or recurrence (patient pain-free at 2h, but experienced recurrence of mild, moderate, or severe migraine pain and took a second dose 2-24h after first dose). Randomization to second dose occurred at baseline; patients originally assigned lasmiditan were randomized to the same lasmiditan dose or placebo (2:1 ratio), and those originally assigned placebo received placebo. Data from SAMURAI and SPARTAN were pooled for efficacy and safety assessment of a second dose of lasmiditan.ResultsThe proportion of patients taking a second dose was lower with lasmiditan versus placebo, and decreased with increasing lasmiditan dose; the majority who took a second dose did so for rescue. In patients taking lasmiditan as first dose, outcomes (pain free, most bothersome symptom [MBS] free) at 2h after a second dose for rescue were similar whether the second dose was lasmiditan or placebo (p>0.05 in all cases). In patients taking lasmiditan for first dose, outcomes at 2h after a second dose for recurrence were as follows: lasmiditan pooled versus placebo - pain free, 50% vs 32% (p>0.05); MBS free, 71% vs 41% (p=0.02); pain relief, 77% vs 52% (p=0.03). In patients whose first dose was lasmiditan, the incidence of treatment emergent adverse events (TEAEs) reported after the second dose was similar whether second dose was lasmiditan or placebo.ConclusionsA second dose of lasmiditan showed some evidence of efficacy when taken for headache recurrence. There was no clear benefit of a second dose of lasmiditan for rescue treatment. The incidences of TEAEs were similar whether the second dose was lasmiditan or placebo.

Background: Lasmiditan, a serotonin 5-HT1F receptor agonist, was effective for acute treatment of patients with migraine in phase 2 studies. We aimed to replicate these findings in a population that includes patients with migraine and cardiovascular risks.

INTRODUCTION:Solanezumab treatment was previously shown to significantly increase total (bound + unbound) cerebrospinal fluid (CSF) levels of amyloid β (Aβ)1-40 and Aβ1-42 in patients with mild to moderate Alzheimer's disease dementia yet did not produce meaningful cognitive effects. This analysis assessed solanezumab's central nervous system target engagement by evaluating changes in CSF total and free Aβ isoforms and their relationship with solanezumab exposure.METHODS:CSF Aβ isoform concentrations were measured in patients with mild Alzheimer's disease dementia from a pooled EXPEDITION + EXPEDITION2 population and from EXPEDITION3. CSF solanezumab concentrations were determined from EXPEDITION3.RESULTS:Solanezumab produced statistically significant increases in CSF total Aβ isoforms versus placebo, which correlated with CSF solanezumab concentration. Inconsistent effects on free Aβ isoforms were observed. Solanezumab penetration into the central nervous system was low.DISCUSSION:Solanezumab administration engaged the central molecular target, and molar ratio analyses demonstrated that higher exposures may further increase CSF total Aβ concentrations.

BACKGROUND Alzheimer's disease is characterized by amyloid-beta (A beta) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble A beta, peptides that may lead to toxic effects in the synapses and precede the deposition of fibrillary amyloid. METHODS We conducted a double-blind, placebo-controlled, phase 3 trial involving patients with mild dementia due to Alzheimer's disease, defined as a Mini-Mental State Examination (MMSE) score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition) and with amyloid deposition shown by means of florbetapir positron-emission tomography or A beta 1-42 measurements in cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment). RESULTS A total of 2129 patients were enrolled, of whom 1057 were assigned to receive solanezumab and 1072 to receive placebo. The mean change from baseline in the ADAS-cog14 score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no significant between-group difference at week 80 (difference, -0.80; 95% confidence interval, -1.73 to 0.14; P = 0.10). As a result of the failure to reach significance with regard to the primary outcome in the prespecified hierarchical analysis, the secondary outcomes were considered to be descriptive and are reported without significance testing. The change from baseline in the MMSE score was -3.17 in the solanezumab group and -3.66 in the placebo group. Adverse cerebral edema or effusion lesions that were observed on magnetic resonance imaging after randomization occurred in 1 patient in the solanezumab group and in 2 in the placebo group. CONCLUSIONS Solanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimer's disease did not significantly affect cognitive decline.

Solanezumab is a humanized monoclonal antibody that preferentially binds soluble amyloid. Its efficacy in treating mild Alzheimer disease (AD), at an intravenous dose of 400mg administered every four weeks, was evaluated in a phase 3, double-blind trial in participants randomized to placebo (N=1072) or solanezumab (N=1057) (EXPEDITION3). Alongside clinical scales, volumetric magnetic resonance imaging (vMRI; in all patients) and cerebrospinal fluid (CSF; in a subset of patients) biomarkers reflecting neurodegenerative processes associated with AD were measured with the aim of assessing solanezumab's effects on longitudinal changes in these markers. 3DT1 scans for vMRI analysis (N=1043 (placebo) and N=1038 (solanezumab)), and CSF samples (N=188–208/arm, depending on the assay), were obtained at baseline and following 80 weeks of treatment. MRI scans were analyzed for hippocampal, entorhinal cortex, ventricular and whole brain volumes using Freesurfer-based methods. Total tau (t-tau) and phospho-tau 181 (p-tau181) concentrations were determined from the CSF samples using validated INNOTEST(R) ELISA assays. An ANCOVA analysis of each biomarker compared the 80-week least square mean change in placebo and solanezumab groups. The right hippocampal volume achieved a nominally statistically significant reduction in the rate of atrophy (p=0.032), corresponding approximately to a 6.7% slowing. Directionally, the other vMRI variables evidenced a reduced rate of atrophy in the solanezumab arm relative to the placebo arm, but these trends did not reach statistical significance (0.077

Solanezumab is a monoclonal antibody that binds to a mid-domain epitope of soluble Aβ. Efficacy of solanezumab (400mg i.v. every four weeks for 80 weeks) was assessed in EXPEDITION3 (NCT01900665), a phase 3, randomized, placebo-controlled, double-blind trial in patients with mild Alzheimer disease (AD) and evidence of amyloid pathology. Solanezumab efficacy in EXPEDITION3 was less than that in a pooled mild AD patient population enrolled in two previous phase 3 trials without regard to amyloid status, (EXPEDITION, NCT00905372; EXPEDITION2, NCT00904683). The present investigation examines central drug target engagement (TE) and pharmacodynamic (PD) activity of solanezumab in EXPEDITION3 and compares both to that in the pooled mild AD population from EXPEDITION/EXPEDITION2. Cerebrospinal fluid (CSF) was obtained at baseline and after 80 weeks of treatment from patients enrolled in an EXPEDITION3 Lumbar Puncture Addendum. Central TE was assessed by treatment effects on CSF total (free plus drug bound) Aβ1–40 and Aβ1–42. Central PD activity was assessed by treatment effects on CSF free (non-drug bound) Aβ1–40 and Aβ1–42. Concentrations of all biomarkers and solanezumab were measured in CSF by validated assays. An ANCOVA analysis of each biomarker compared the 80-week least squares mean change ± S.E. in placebo and solanezumab groups. CSF total Aβ1–40 decreased 1256.4±470.2 pg/mL in the placebo arm (N=120) and increased 3285.6±460.6 pg/mL in the solanezumab arm (N=127) (p<0.001). Total Aβ1–42 decreased 63.2±31.3 pg/mL in the placebo arm (n=123) and increased 459.6±31.1 pg/mL in the solanezumab arm (N=131) (p<0.001). CSF free Aβ1–40 decreased 320.0±182.5 pg/mL in the placebo arm (N=123) and decreased 714.6±177.8 pg/mL in the solanezumab arm (N=131) (p=0.07). Free Aβ1–42 decreased 9.3±8.2 pg/mL in the placebo arm (N=103) and decreased 37.3±7.5 pg/mL in the solanezumab arm (N=116) (p=0.005). In EXPEDITION3, solanezumab central TE was demonstrated with respect to both total Aβ1–40 and Aβ1–42. These effects were consistent with those observed in EXPEDITION/EXPEDITION2 and correlated with CSF solanezumab exposure. Solanezumab central target-related PD activity was significant as assessed by CSF free Aβ1–42 but not free Aβ1–40. The differences observed for free Aβ1–40 and Aβ1–42 between EXPEDITION/EXPXPEDITION2 and EXPEDITION3 are complex and will be further discussed.

Little research has been conducted on the statistical properties of composite measures comprising linear combinations of continuous component scales. We assessed the quantitative relationship between the composites and their individual components regarding their abilities to detect treatment effects. In particular, we developed the mathematical derivation of the treatment effect size of a continuous composite in relation to the treatment effect sizes of its components and proved multiple properties of the composite. We demonstrated that the treatment effect size of a composite is greater than the minimum treatment effect size of its components and that above certain thresholds of correlations of components and ratios of component effect sizes, the composite may outperform its components. Examples from Alzheimer's disease (AD) clinical studies of solanezumab and donepezil using the composite Integrated AD Rating Scale (iADRS) and its components, the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and AD Cooperative Study-Activities of Daily Living inventory, instrumental items (ADCS-iADL) were consistent with the theoretical statistical properties. The understanding of the quantitative relationships between continuous composites and their components will be useful in clinical trial design and the development of new scales and composites across therapeutic areas.

EXPEDITION3 was a placebo-controlled Phase 3 study assessing the effect of solanezumab (a monoclonal antibody that binds soluble amyloid-beta peptides) on cognitive decline over 80 weeks in patients with mild Alzheimer's disease (AD). Topline results showed EXPEDITION 3 did not meet its primary endpoint. A large subset of subjects underwent amyloid PET imaging with florbetapir F 18, and a smaller subset of those also underwent tau PET imaging with flortaucipir F 18. Amyloid PET scanning (20 min scans, 50 min post injection 10 mCi florbetapir F 18) was done at screening and at week 80. SUVr values were calculated from standard atlas-based cortical and whole cerebellar regions. Longitudinal measures were normalized by a subject-specific MRI-derived white matter region to reduce variability in longitudinal amyloid PET estimate. Tau PET scanning (30 min scans, 75 min post injection of 6.5 mCi flortaucipir F 18, aka AV-1451) was done at baseline, week 40 and week 80. Flortaucipir SUVr was calculated from a large atlas-based cortical region normalized by a parametrically derived subject-specific white matter reference region. In this initial analysis, solanezumab treatment effects on florbetapir amyloid and flortaucipir tau PET imaging were evaluated with analysis of co-variance (ANCOVA) and mixed effects model repeated measurement (MMRM), respectively. The association of baseline florbetapir amyloid and flortaucipir tau PET to cognitive and functional decline in the placebo arm was also evaluated. There was no significant difference between solanezumab (n=791) vs placebo (n=805) on change in amyloid SUVr by florbetapir PET (p=0.131). There was a significant increase of flortaucipir PET SUVr over the 80 week study, but there was no significant difference (p=0.685) between solanezumab (n=107) vs placebo (n=97). In the placebo arm, the subgroups with higher levels of baseline tau SUVr, but not amyloid SUVr, declined significantly more (p< 0.05) on ADAS-Cog14 and MMSE, but not on CDR sum of boxes. PET imaging biomarkers are playing an increasing role in better characterizing the enrolled population and understanding the downstream impact of therapeutic drugs on underlying AD pathology. Initial analyses of EXPEDITION 3 data supports the hypothesis that flortaucipir PET may stratify risk of cognitive decline during the trial.