PURPOSE:To evaluate MK-1942, a negative allosteric modulator of mGluR2, for treatment-resistant depression using chronic and intermittent dosing. METHODS:Randomized, double-blind, 4-week study of MK-1942 added to stable antidepressant therapy in adults with treatment-resistant depression (NCT04663321). Participants were randomized 2:1:2 to (1) daily MK-1942 titrated from 5 to 20 mg bid, (2) twice-weekly MK-1942 10 mg, or (3) placebo. The endpoints were Montgomery Asberg Depression Rating Scale (MADRS) scores at week 3 (daily MK-1942) and week 1 (twice-weekly MK-1942). RESULTS:The study was terminated following asymptomatic elevations in liver function tests. At termination, ~70% of the planned enrolment was achieved (MK-1942 daily N=40, MK-1942 twice-weekly N=19, placebo N=40). No significant efficacy differences from placebo were seen for either MK-1942 group. The difference in mean change-from-baseline MADRS score for daily MK-1942 vs placebo directionally favored placebo at Week 3 (3.3 [95% CI: -1.4, 8.0]) and all other time points. The difference between twice-weekly MK-1942 and placebo directionally favored placebo at week 1 (1.9 [95% CI: -2.7, 6.4]) but not at later time points (eg, week 4, -1.5 [95% CI: -8.0, 4.9]). Interestingly, at every time point, the difference between twice-weekly and daily MK-1942 directionally favored the twice-weekly group. Discontinuations due to an adverse event were more common with MK-1942 than placebo (daily=10.0%, twice-weekly=15.8%, placebo=2.5%), and dizziness was the most common adverse event (daily=25.0%, twice-weekly=31.6%, placebo=7.5%). CONCLUSIONS:Although interpretation of the findings is limited by the early termination of the trial, MK-1942 was not effective in treatment-resistant depression.

BACKGROUND:PDE10A inhibition represents a potential mechanism for treating schizophrenia. A 12-mg dose of the PDE10A inhibitor MK-8189 showed initial evidence of efficacy for improving schizophrenia symptoms after 4 weeks. We performed a follow-up study evaluating higher MK-8189 doses (16 mg and 24 mg, predicted to produce up to 80% sustained enzyme occupancy) over 6 weeks. METHODS:Randomized, double-blind, phase 2b study consisting of a 6-week acute treatment period and a 6-week extension (NCT04624243). Participants were diagnosed with schizophrenia and were experiencing active phase symptoms. For the acute treatment period, participants were randomized in a 2:2:2:1:2 ratio to 6 weeks of daily MK-8189 8 mg (dropped after a third of participants had been enrolled), 16 mg, 24 mg, risperidone 6 mg (for assay sensitivity), or placebo. The primary outcome was the change from baseline in Positive and Negative Syndrome Scale (PANSS) total score at 6 weeks. RESULTS:The number of treated participants in the acute period was: MK-8189 16 mg, N=132; MK-8189 24 mg, N=132; risperidone 6 mg, N=65; and placebo, N=129. MK-8189 16 mg and 24 mg did not show an improvement versus placebo for change-from-baseline in PANSS total score after 6 weeks [16 mg-placebo difference, -2.8 (95% CI: -8.3,2.6), P =0.241; 24 mg-placebo difference, -0.7 (95% CI: -6.3,4.9), P =0.784], whereas risperidone did [risperidone-placebo difference, -6.2 (95% CI: -12.9,0.6), P =0.040]. Over the 6-week acute period, more participants discontinued treatment due to an adverse event in the MK-8189 24 mg group (25.0%) than in the MK-8189 16 mg (12.9%), risperidone (12.3%) or placebo (12.4%) groups. CONCLUSIONS:These findings suggest that PDE10A inhibition does not have antipsychotic effects at the doses tested.

INTRODUCTION:Effect on amyloid plaque as measured by positron emission tomography imaging with Centiloid standardization of two therapeutic approaches targeting amyloid beta (Aβ) was investigated using exposure-response modeling. METHODS:Individual-level verubecestat data from the APECS trial were pooled with summary-level data from the literature for amyloid monoclonal antibodies (mAbs) and fitted in a joint non-linear mixed-effects model. RESULTS:An indirect-response (turnover) model with verubecestat inhibiting plaque formation and mAbs stimulating plaque removal well represented the data. The estimated plaque elimination half-life was 6.4 years. Daily verubecestat 40 mg was estimated to reduce formation by 91.8%. Aducanumab 10 mg/kg every 4 weeks (Q4W), donanemab 1400 mg Q4W, gantenerumab 1200 mg Q4W, and lecanemab 10 mg/kg Q2W were estimated to increase the removal rate by 9.3-, 18.6-, 5.3-, and 13.8-fold, respectively. DISCUSSION:The model provides a fundamental measure of drug effects on plaque, independent of disease stage and study-design factors, improving cross-study comparisons and enabling predictions. Highlights:The plaque turnover model describes natural progression and BACE and mAb intervention.The model estimation of the underlying plaque elimination half-life is 6.4 years.Approach improves cross-study comparison independently of population and study design.Predictions of alternative regimens/therapeutic approaches will aid future study design.

Recent positive results of three phase III anti-amyloid monoclonal antibody trials are transforming the landscape of disease-modifying therapeutics for Alzheimer’s disease, following several decades of failures. Indeed, all three trials have met their primary endpoints. However, the absolute size of the benefit measured in these trials has generated a debate on whether the change scores observed on clinical outcome assessments represent a clinically meaningful benefit to patients. An evidence-based conclusion is urgently required to inform decision-making related to the approval, reimbursement, and ultimately, the management of emerging therapies in clinical practice. The EU-US CTAD Task Force met in Boston to address this important question. The current state-of-the-art knowledge for interpreting clinical meaningfulness of AD clinical trial results, including the point of view of patients and study partners on what is clinically meaningful, was discussed and is summarized here. A combination of methodologies to address the challenges emerged. There remain gaps in the understanding of clinical meaningfulness that only long-term longitudinal studies will be able to address.

Background: PDE10A inhibition represents a potential mechanism for treating schizophrenia. PDE10A inhibitors increase cyclic nucleotides in striatal neurons, thereby mimicking the effects of dopamine receptor D2 antagonists and D1 agonists. We evaluated the PDE10A inhibitor MK-8189 for treating schizophrenia. Methods: Randomized, double-blind, placebo and active-controlled, phase 2a, multicenter, inpatient trial in adults experiencing an acute episode of schizophrenia. Participants were randomized 2:2:1 to once-daily MK-8189 12 mg, placebo, or risperidone 6 mg (active control) for 4-weeks. The primary outcome was change-from-baseline in total score on the Positive and Negative Syndrome Scale (PANSS) at 4 weeks. Results: The number of treated participants was 90 for MK-8189, 89 for placebo, and 45 for risperidone. MK-8189 demonstrated a trend towards improvement versus placebo for change-from-baseline in PANSS total score after 4 weeks (difference = -4.7 [95 % CI: -9.8,0.5], P = 0.074). The active control risperidone was superior to placebo on PANNS total score (difference = -7.3 [95 % CI: -14.0,-0.6], P = 0.033), demonstrating assay sensitivity, while MK-8189 and risperidone did not significantly differ (difference = 2.6 [95 % CI: -4.0,9.2], P = 0.440). MK-8189 had a nominally significant effect on PANSS positive subscale score compared to placebo (difference = -2.2 [95 % CI: -3.8,-0.5], P = 0.011). Discontinuation of MK-8189 treatment due to an adverse event was low (<10 %). Extrapyramidal symptoms occurred with MK-8189 but were mostly mild and transient. Compared with placebo, MK-8189 reduced body weight while risperidone increased weight. Conclusions: These findings suggest that PDE10A inhibition may produce antipsychotic effects and associated weight loss and that further trials with PDE10A inhibitors are warranted.

The International CTAD Task Force (TF) addressed challenges related to designing clinical trials for agitation in dementia, presenting accomplishments from the two previous TFs on neuropsychiatric symptoms (NPS). In addition, this TF proposed a paradigm shift in NPS assessment and management, presenting Mild Behavioral Impairment (MBI) as a clinical syndrome. MBI is marked by later-life emergent and persistent NPS in dementia-free older persons (ranging from cognitively unimpaired to subjective cognitive decline to mild cognitive impairment), which facilitates earlier detection and better prognostication of Alzheimer's disease (AD). The TF has made the following recommendations for incorporation of NPS into AD preventative trials: (1) clinical trials targeting improvement in MBI symptoms should be undertaken; (2) treatment trials for MBI should be disease specific and confirm the diagnosis of participants using biomarkers; trials should include measures sensitive to cognitive changes in preclinical AD, which can serve as outcome measures, in addition to changes in biomarker levels; (3) as a first step, pharmacotherapeutic trials should address the full MBI complex as well as the specific symptoms/domains that constitute MBI; (4) clinical trials using problemadaptation psychotherapy to target affective MBI should be considered; and (5) MBI should be considered in AD trials of disease modifying therapies. The well-validated and widely-used MBI Checklist (MBI-C) is an appropriate symptom rating scale for these studies, as it was developed specifically to identify and measure MBI in dementia-free persons. Other scales such as the Neuropsychiatric Inventory (NPI) may be used, although administration at two timepoints may be necessary to operationalize the MBI criterion of symptom persistence.

In randomized clinical trials (RCTs) for Alzheimer’s Disease (AD), cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers are currently used for the detection and monitoring of AD pathological features. The use of less resource-intensive plasma biomarkers could decrease the burden to study volunteers and limit costs and time for study enrollment. Blood-based markers (BBMs) could thus play an important role in improving the design and the conduct of RCTs on AD. It remains to be determined if the data available on BBMs are strong enough to replace CSF and PET biomarkers as entry criteria and monitoring tools in RCTs.

BACKGROUND:HIV subtypes B and C together account for around 60% of HIV-1 cases worldwide. We evaluated the safety and immunogenicity of a subtype B DNA vaccine prime followed by a subtype C viral vector boost. METHODS:Fourteen healthy adults received DNA plasmid encoding HIV-1 subtype B nef/tat/vif and env (n = 11) or placebo (n = 3) intramuscularly (IM) via electroporation (EP) at 0, 1, and 3 months, followed by IM injection of recombinant vesicular stomatitis virus encoding subtype C Env or placebo at 6 and 9 months. Participants were assessed for safety, tolerability of EP, and Env-specific T-cell and antibody responses. RESULTS:EP was generally well tolerated, although some device-related adverse events did occur, and vaccine reactogenicity was mild to moderate. The vaccine stimulated Env-specific CD4 + T-cell responses in greater than 80% of recipients, and CD8 + T-cell responses in 30%. Subtype C Env-specific IgG binding antibodies (bAb) were elicited in all vaccine recipients, and antibody-dependent cell-mediated cytotoxicity (ADCC) responses to vaccine-matched subtype C targets in 80%. Negligible V1/V2 and neutralizing antibody (nAb) responses were detected. CONCLUSIONS:This prime/boost regimen was safe and tolerable, with some device-related events, and immunogenic. Although immunogenicity missed targets for an HIV vaccine, the DNA/rVSV platform may be useful for other applications. TRIAL REGISTRATION: CLINICALTRIALS:gov: NCT02654080.

BACKGROUND:Delay of progression from prodromal Alzheimer's disease (AD) to dementia is an important outcome in AD trials. Centralized adjudication is intended to improve the consistency of dementia diagnosis but has not been scrutinized.OBJECTIVE:To evaluate centralized adjudication for determining progression to dementia compared with Site Investigator opinion or change in Clinical Dementia Rating (CDR).METHODS:We used data from the 2-year APECS trial of verubecestat versus placebo in 1,451 prodromal AD participants. Cases were triggered for central adjudication if: 1) the Site Investigator judged the participant had progressed to dementia, or 2) the participant's CDR sum-of-boxes score increased ≥2 points from baseline. Post-hoc analyses were performed on pooled treatment-group data to compare methods of assessing progression.RESULTS:581/1,451 (40%) participants had changes triggering adjudication and most (83%) were confirmed as progression to dementia. Only 66% of those who met CDR criteria (regardless of whether they also met Site Investigator criteria) were adjudicated to have progressed to dementia and just 15% of those who met only CDR criteria were adjudicated to have progressed, representing 5% of progressors. In contrast, 99% of those who met Site Investigator criteria (regardless of whether they also met CDR criteria) were adjudicated to have progressed, and the same was true for those who met only Site Investigator criteria.CONCLUSION:A positive Site Investigator opinion is an excellent predictor for a positive adjudication decision regarding onset of dementia. Conversely, sole use of CDR sum-of-boxes change ≥2 is inadequate. The benefit of centralized adjudication appears doubtful.

The BACE inhibitor verubecestat (MK-8931) at doses of 12 and 40 mg demonstrated cognitive and functional decline relative to placebo in a Phase 3 trial of prodromal AD (APECS, NCT01953601) and no effect on progression in a Phase 3 trial of mild-to-moderate AD (EPOCH, NCT01739348). Disease progression modeling was used to investigate the temporal pattern of the cognitive and functional drug effects and to explore covariate, dose- or exposure-dependency in the pooled data from both trials. The key objective was to determine whether the rate of progression was slowed by BACEi but obscured by an early detrimental drug effect. Disease progression models for the clinical efficacy outcomes (ADAS-cog11, CDR-SB) were developed using similar methodology to an established ADAS-cog disease progression model (Ref). Parameters describing placebo response were first estimated. Akaike Information Criteria (AIC) were then used to select among potential drug effects (effects on progression rate and/or early detrimental offset) and to test for dependencies on dose, drug exposure, and patient characteristics. A simulation exercise confirmed that a true 25% or 50% reduction in the progression rate with treatment could be reliably identified in the setting of the early detrimental effect. Results were generally concordant across ADAS-cog11 and CDR-SB. An early symptomatic (detrimental offset) response was identified with verubecestat; no effect on rate of disease progression was supported. The magnitude of the drug effect offset was estimated 1.8 for ADAS-cog11 and 0.33 for CDR-SB. Covariates were generally concordant across measures with disease severity at baseline identified for both progression rate and detrimental offsetting. Additionally, age, weight, geographic region, and education effects were identified on progression. Threshold analysis of the detrimental offsetting effect suggested that the effect was present in less severe disease but absent in the most advanced AD patients (ADAS-cog11 baseline>24 and CDR-SB baseline > = 12). No dose or AUC dependency on the detrimental offsetting effect of verubecestat was found, indicating that the maximum effect is achieved at 12 and 40 mg doses. There was no evidence supporting a slowed rate of disease progression by BACEi after accounting for the early detrimental drug effect.

In-clinic venous dried blood spot (DBS) pharmacokinetic (PK) sampling was incorporated into two phase 3 studies of verubecestat for Alzheimer’s disease (EPOCH [NCT01739348] and APECS [NCT01953601]), as a potential alternative to plasma PK sampling. Initially, plasma and DBS PK samples were collected concurrently to better understand the DBS–plasma verubecestat concentration relationship, with the intention of discontinuing DBS or plasma sampling following interim analysis. Following initial analyses and comparison of results with prespecified selection criteria, plasma PK sampling was discontinued; however, a stability issue resulting in generally lower DBS verubecestat concentrations with longer collection-to-assay times was subsequently discovered (associated with non-compliance in DBS sample handling), prompting reintroduction of plasma sampling. To enable inclusion of DBS data in population PK analyses, a conversion algorithm for calculating plasma-equivalent concentrations (accounting for DBS sample instability) was developed using paired (time-matched) plasma and DBS data from the EPOCH study. Verubecestat population PK models developed from pooled phase 1/1b and EPOCH data using either (1) plasma-only data or (2) plasma and plasma-equivalent concentrations (calculated from non-paired DBS samples) yielded similar results. The algorithm robustness was demonstrated using DBS data from paired samples from the APECS study and comparison between plasma and plasma-equivalent concentrations. The population PK model was updated with APECS data (both plasma and, if no plasma sample available, plasma equivalents). The results demonstrated similar PK in the two phase 3 populations and exposures consistent with expectations from phase 1 data. This case study illustrates challenges with employing new sampling techniques in large, global trials and describes lessons learned.

PDE10A inhibitors target signaling molecules that regulate activity of the striatum in schizophrenia. We report here on initial clinical findings with the PDE10A inhibitor MK-8189.

BACKGROUND:We performed exploratory analyses of retinal thickness data from a clinical trial of the AβPP cleaving enzyme (BACE) inhibitor verubecestat in patients with Alzheimer's disease (AD).OBJECTIVE:To evaluate: 1) possible retinal thickness changes following BACE inhibition; and 2) possible association between retinal thickness and brain atrophy.METHODS:Retinal thickness was measured using spectral-domain optical coherence tomography in a 78-week randomized placebo-controlled trial of verubecestat in 1,785 patients with mild-to-moderate AD. Changes from baseline in retinal pigment epithelium, macular grid retinal nerve fiber layer, central subfield retinal thickness, and macular grid volume were evaluated for verubecestat versus placebo. Correlation analyses were performed to investigate the potential association between macular grid retinal nerve fiber layer and central subfield retinal thickness with brain volumetric magnetic resonance imaging (vMRI) data at baseline, as well as correlations for changes from baseline at Week 78 in patients receiving placebo.RESULTS:Verubecestat did not significantly alter retinal thickness during the trial compared with placebo. At baseline, mean macular grid retinal nerve fiber layer and central subfield retinal thickness were weakly but significantly correlated (Pearson's r values≤0.23, p-values < 0.01) with vMRI of several brain regions including whole brain, hippocampus, and thalamus. At Week 78, correlations between retinal thickness and brain vMRI changes from baseline in the placebo group were small and mostly not statistically significant.CONCLUSION:BACE inhibition by verubecestat was not associated with adverse effects on retinal thickness in patients with mild-to-moderate AD. Correlations between retinal thickness and brain volume were observed at baseline.TRIAL REGISTRATION:Clinicaltrials.gov NCT01739348 (registered December 3, 2012; https://clinicaltrials.gov/ct2/show/NCT01739348).

In the phase 3 EPOCH trial (Clinicaltrials.gov; NCT01739348), treatment with the BACE inhibitor verubecestat failed to improve cognition in patients with mild-to-moderate Alzheimer's disease, but was associated with reduced hippocampal volume after 78 weeks as assessed by MRI. The aims of the present exploratory analyses were to: (i) characterize the effect of verubecestat on brain volume by evaluating the time course of volumetric MRI changes for a variety of brain regions; and (ii) understand the mechanism through which verubecestat might cause hippocampal (and other brain region) volume loss by assessing its relationship to measures of amyloid, neurodegeneration, and cognition. Participants were aged 55-85 years with probable Alzheimer's disease dementia and a Mini Mental State Examination score ≥15 and ≤26. MRIs were obtained at baseline and at Weeks 13, 26, 52 and 78 of treatment. MRIs were segmented using Freesurfer and analysed using a tensor-based morphometry method. PET amyloid data were obtained with 18F-flutemetamol (Vizamyl®) at baseline and Week 78. Standardized uptake value ratios were generated with subcortical white matter as a reference region. Neurofilament light chain in the CSF was assessed as a biomarker of neurodegeneration. Compared with placebo, verubecestat showed increased MRI brain volume loss at Week 13 with no evidence of additional loss through Week 78. The verubecestat-related volumetric MRI loss occurred predominantly in amyloid-rich brain regions. Correlations between amyloid burden at baseline and verubecestat-related volumetric MRI reductions were not significant (r = 0.05 to 0.26, P-values > 0.27). There were no significant differences between verubecestat and placebo in changes from baseline in CSF levels of neurofilament light chain at Week 78 (increases of 7.2 and 14.6 pg/ml for verubecestat versus 19.7 pg/ml for placebo, P-values ≥ 0.1). There was a moderate correlation between volumetric MRI changes and cognitive decline in all groups including placebo at Week 78 (e.g. r = -0.45 to -0.55, P < 0.001 for whole brain), but the correlations were smaller at Week 13 and significant only for the verubecestat groups (e.g. r = -0.15 and -0.11, P < 0.04 for whole brain). Our results suggest that the verubecestat-associated MRI brain volume loss is not due to generalized, progressive neurodegeneration, but may be mediated by specific effects on BACE-related amyloid processes.

Introduction: The APECS and AMARANTH trials showed that beta-secretase (BACE) inhibitors verubecestat and lanabecestat failed to slow cognitive and functional decline in individuals with prodromal or early Alzheimer's disease. Here, the performance on secondary and exploratory cognitive measures in both studies is reported. Methods: APECS (verubecestat) and AMARANTH (lanabecestat) were randomized, double-blind, placebo-controlled, parallel-group, 104-week clinical trials conducted by different sponsors. Measures included the 3-Domain Composite Cognition Score (CCS-3D), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), Letter/Category Fluency, and Digit Symbol Coding. Results: Verubecestat showed worsening on the CCS-3D Total Score, Episodic Memory, and Attention/Processing Speed domains. Lanabecestat showed worsening on the RBANS Total Score, Immediate Memory, and Visuospatial/Constructional Indexes. Both BACE inhibitors showed worsening on Digit Symbol Coding and improvements on Letter/Category Fluency. Discussion: In both studies, many measures showed treatment-associated cognitive worsening, whereas verbal fluency tasks showed improvement.

Treatment with BACE inhibitor verubecestat 12mg and 40mg failed to improve cognition in mild-to-moderate AD patients but was associated with reduced MRI brain volume on volumetric measures. To explore this observed effect, we performed kinetic analyses of volumetric MRI changes in different brain regions and assessed the contribution of amyloid load and disease-related neurodegeneration. Participants (age 55–85 years, inclusive) with probable AD and an MMSE score ≥15 and ≤26 were enrolled. MRI scans were obtained at baseline and at weeks 13, 26, 52 and 78 of the treatment period. 3D T1-weighted MRI images were segmented using Freesurfer and analyzed using a tensor based morphometry method. PET amyloid data were obtained with Vizamyl at baseline and week-78. SUVR values were generated with subcortical white matter as a reference region. Compared with placebo, kinetic analysis of 20 brain regions positive for amyloid showed an increased MRI volume loss in both verubecestat dose groups in all regions at week-13 with no evidence of further loss relative to placebo through week-78. Correlation analysis did not show a relationship between verubecestat-related volume reductions at week-13 and week-78 and amyloid burden at baseline. Analysis of 29 brain regions categorized by Vizamyl imaging as amyloid positive or negative showed that verubecestat-related volume loss at week-13 was present only in amyloid positive regions. The degree of AD-related neurodegeneration in the placebo group (change in MRI volume from baseline at week-78) was estimated in 31 brain regions. Verubecestat-related volume loss at week-13 within a region was not related to the magnitude of disease-related regional neurodegeneration in the placebo group. Finally, MRI volume changes at week-13 showed no conclusive relationship with ADAS-Cog11 total score. Kinetic analyses of verubecestat-induced brain volume loss demonstrate that this effect occurs rapidly and only in brain regions with amyloid pathology. However, this regional effect does not appear to be correlated with the magnitude of disease-related neurodegeneration or cognitive impairment. These results suggest that verubecestat is not associated with a generalized, widespread or progressive neurotoxic effect but may exert specific effects on amyloid related processes.

The BACE inhibitor verubecestat (MK-8931) demonstrated cognitive and functional decline relative to placebo in a 2-year Phase 3 trial of individuals with prodromal AD (APECS; NCT01953601), along with reductions in brain volume and amyloid plaque. Disease progression modeling has demonstrated a lack of dose- or exposure-dependency in the clinical cognition and function endpoints (see separate abstract). In this analysis, pharmacokinetic (PK) and safety and biomarker data from the trial were examined to characterize target engagement and biomarker exposure-response. Plasma and/or Dried-Blood-Spot samples were collected during 4–7 visits for determination of verubecestat concentrations (4,050 samples from 963 participants). Drug exposure (AUC, Cmax, Ctrough) was estimated using a population PK modeling approach. Exposure-response relationships for select adverse events (AEs), volumetric MRI and PET amyloid assessments from brain scans versus AUC were evaluated graphically and utilizing exposure-response models. Linear logistic regression models were applied to AE terms or group terms to test for exposure-related incidence rates within the subset treated with verubecestat. Mean (SD) AUC was 1.56 (0.32) and 5.15 (1.10) μM·h, respectively in the 12 mg (n=483) and 40 mg (n=480) verubecestat arms, consistent with previous data. No statistically significant exposure-dependencies were identified for the AE terms or group terms examined. Total brain volume demonstrate exposure-dependency at Week 13 (EC50 = 1.3 μM·h) and a similar relationship was seen at end of treatment (Week 104). PET amyloid (SUVR) data from Week 104 demonstrated a strong exposure-dependency (EC50 = 0.5 μM·h) consistent with reduced plaque with treatment compared to gain in plaque on placebo. A dose of 1.8 mg (∼27% inhibition of CSF Aβ40) was predicted to correspond to stable plaque levels. These results indicate that APECS tested drug exposures previously associated with 67% and 84% average inhibition of CSF Aβ40 at the 12 and 40 mg doses, respectively [1]. Exposure-dependency in both treatment-related brain volume loss and in reduction in amyloid plaque load was identified in the APECS data; however, these differences in biomarkers were not associated with exposure-dependency in cognition, function, or safety outcomes. Reference: 1 Kennedy et al., Sci. Transl. Med. 8, 363ra150 (2016).