Framtiden inom utredning, diagnostik och behandling

Sebastian PalmqvistLeg. läkare, Med. dr.

Docent i Neurovetenskap

Neurologiska klinikenSkånes Universitetssjukhus

Enheten för klinisk minnesforskningLunds Universitet

demens

kognitiv sjukdom

Kognitiv sjukdom• Varaktig försämring av tankeförmågan inom minst

ett område baserat på:1. Patient, nära anhörig eller kliniker och2. kognitiv testning

• Den kognitiva svikten påverkar dagliga aktiviteter

• Uppträder inte enbart under pågående förvirring

• Förklaras inte bättre av annan psykisk sjukdom (schizofreni, depression etc)

Kognitiv sjukdom kopplas till

• Alzheimers sjukdom

• Frontotemporal lobär degeneration

• Lewy body sjukdom

• Vaskulär sjukdom

• Traumatisk hjärnskada

• Substans/läkemedels användning

• HIV

• Prionsjukdom

• Parkinson

• Huntington

• Annat medicinskt tillstånd

• Multipla etiologier

• Ospecificerat

• Viktigt med specifik demensdiagnos!

• Utan diagnos: sämre omhändertagande och behandling

• Felaktig specifik diagnos: ökade kostnader och ökat lidande.

AAIC Jul 17, 2013

utredning idag 50% får bara symtomdiagnos (”demens”)

upp till 50% får fel diagnos i primärvård nya diagnostiska metoder

Amyloid PETVisar om man har beta-amyloid plack i hjärnan

Lindriga minnesbesvär

Fick senare depressionsdiagnos

Lindriga minnesbesvär

Utvecklade Alzheimer

demens efter 2 år

Tau PETVisar om man har tau patologi i hjärnan

Frisk äldre

Lindriga minnesbesvär

visade sig sen ha Alzheimer

Tau PET Ämnesomsättning Amyloid PET MR-kamera

R Smith, O Hansson et al., Minneskliniken, Malmö, SUS

Varianter av Alzheimer• Amnestisk (>90%) - påverkar minnet först

• Icke-amnestisk - ofta påverkan på praktisk förmåga och visuospatial förmåga

• Logopen variant - språkförmåga försämras

• Posterior kortikal atrofi (PCA) - Syntolkning och visuospatial förmåga

• Beteendevariant - beteendestörningar

Voxelwise contrasts betweenpatients and control subjects

Next, we performed voxelwise contrasts for 18F-AV1451,11C-PiB and 18F-FDG between patients with posterior cor-tical atrophy and controls. In line with our hypothesis anda previous case study (Ossenkoppele et al., 2015d), pa-tients with PCA showed substantial inverse spatial overlapbetween greater 18F-AV1451 and reduced 18F-FDGuptake, specifically affecting brain regions implicated inhigher-order visual processing, particularly in the righthemisphere (Fig. 2A). This is further illustrated by over-laying the binarized 18F-AV1451 and 18F-FDG significancemaps (Fig. 2D). Additionally, 18F-AV1451 uptake was ele-vated in several brain regions where 18F-FDG uptake didnot differ from controls, including primary visual cortexand posterior cortex in the left hemisphere. Contraryto the regional specificity of 18F-AV1451 and 18F-FDG,11C-PiB retention was distributed throughout the neocor-tex and implicated both clinically affected and relativelyspared regions (e.g. extensive binding in frontal cortex;Fig. 2A).

In line with the clinical presentation, the 18F-AV1451 pat-tern in patients with an amnestic-predominant presentationmost prominently affected the medial temporal lobes and lat-eral temporoparietal cortex (Fig. 2B). When assessing theparametric images and AIs of the five logopenic variantPPA cases individually, three patients showed the predictedleft4 right asymmetry, one was fairly symmetric, and oneshowed right4 left 18F-AV1451 uptake (Table 2 andFig. 2E). Notably, the two patients with most advanced dis-ease severity showed the greatest 18F-AV1451 uptake in theright hemisphere and in anterior brain regions. On group-levelvoxelwise analyses, the 18F-AV1451 pattern in patients withlogopenic variant PPA was rather symmetric, with uptakemainly observed in bilateral temporoparietal regions that aretypically involved in language function (Fig. 2C). Voxelwise11C-PiB and 18F-FDG contrasts between amnestic Alzheimer’sdisease and logopenic variant PPA patients against controlsare shown in Supplementary Fig. 3. In general, the results aresimilar to those seen in patients with PCA (i.e. widespreadneocortical 11C-PiB binding, while 18F-FDG uptake is moreregion-specific), but should be interpreted with caution giventhe smaller sample size due to missing scans.

Figure 1 18F-AV1451 uptake in individuals with distinct phenotypes of Alzheimer’s disease. SUVR 18F-AV1451 images (neurological

orientation) in (A) a 59-year-old female (MMSE: 28) with posterior cortical atrophy [note that this a different patient than presented in

Ossenkoppele et al. (2015d)]; (B) a 77-year-old female (MMSE: 17) with logopenic variant PPA; (C) a 71-year-old female (MMSE: 23) with amnestic

Alzheimer’s disease; (D) a 59-year-old female (MMSE: 27) with non-amnestic Alzheimer’s disease; (E) a 59-year-old male (MMSE: 21) with a

behavioural presentation of Alzheimer’s disease, and (F) a 60-year-old female (MMSE: 16) with a corticobasal syndrome affecting the left

hemibody.

In vivo tau PET in Alzheimer’s disease BRAIN 2016: 139; 1551–1567 | 1557

by guest on May 23, 2016

http://brain.oxfordjournals.org/D

ownloaded from

Voxelwise contrasts betweenpatients and control subjects

Next, we performed voxelwise contrasts for 18F-AV1451,11C-PiB and 18F-FDG between patients with posterior cor-tical atrophy and controls. In line with our hypothesis anda previous case study (Ossenkoppele et al., 2015d), pa-tients with PCA showed substantial inverse spatial overlapbetween greater 18F-AV1451 and reduced 18F-FDGuptake, specifically affecting brain regions implicated inhigher-order visual processing, particularly in the righthemisphere (Fig. 2A). This is further illustrated by over-laying the binarized 18F-AV1451 and 18F-FDG significancemaps (Fig. 2D). Additionally, 18F-AV1451 uptake was ele-vated in several brain regions where 18F-FDG uptake didnot differ from controls, including primary visual cortexand posterior cortex in the left hemisphere. Contraryto the regional specificity of 18F-AV1451 and 18F-FDG,11C-PiB retention was distributed throughout the neocor-tex and implicated both clinically affected and relativelyspared regions (e.g. extensive binding in frontal cortex;Fig. 2A).

In line with the clinical presentation, the 18F-AV1451 pat-tern in patients with an amnestic-predominant presentationmost prominently affected the medial temporal lobes and lat-eral temporoparietal cortex (Fig. 2B). When assessing theparametric images and AIs of the five logopenic variantPPA cases individually, three patients showed the predictedleft4 right asymmetry, one was fairly symmetric, and oneshowed right4 left 18F-AV1451 uptake (Table 2 andFig. 2E). Notably, the two patients with most advanced dis-ease severity showed the greatest 18F-AV1451 uptake in theright hemisphere and in anterior brain regions. On group-levelvoxelwise analyses, the 18F-AV1451 pattern in patients withlogopenic variant PPA was rather symmetric, with uptakemainly observed in bilateral temporoparietal regions that aretypically involved in language function (Fig. 2C). Voxelwise11C-PiB and 18F-FDG contrasts between amnestic Alzheimer’sdisease and logopenic variant PPA patients against controlsare shown in Supplementary Fig. 3. In general, the results aresimilar to those seen in patients with PCA (i.e. widespreadneocortical 11C-PiB binding, while 18F-FDG uptake is moreregion-specific), but should be interpreted with caution giventhe smaller sample size due to missing scans.

Figure 1 18F-AV1451 uptake in individuals with distinct phenotypes of Alzheimer’s disease. SUVR 18F-AV1451 images (neurological

orientation) in (A) a 59-year-old female (MMSE: 28) with posterior cortical atrophy [note that this a different patient than presented in

Ossenkoppele et al. (2015d)]; (B) a 77-year-old female (MMSE: 17) with logopenic variant PPA; (C) a 71-year-old female (MMSE: 23) with amnestic

Alzheimer’s disease; (D) a 59-year-old female (MMSE: 27) with non-amnestic Alzheimer’s disease; (E) a 59-year-old male (MMSE: 21) with a

behavioural presentation of Alzheimer’s disease, and (F) a 60-year-old female (MMSE: 16) with a corticobasal syndrome affecting the left

hemibody.

In vivo tau PET in Alzheimer’s disease BRAIN 2016: 139; 1551–1567 | 1557

by guest on May 23, 2016

http://brain.oxfordjournals.org/D

ownloaded from

Voxelwise contrasts betweenpatients and control subjects

Next, we performed voxelwise contrasts for 18F-AV1451,11C-PiB and 18F-FDG between patients with posterior cor-tical atrophy and controls. In line with our hypothesis anda previous case study (Ossenkoppele et al., 2015d), pa-tients with PCA showed substantial inverse spatial overlapbetween greater 18F-AV1451 and reduced 18F-FDGuptake, specifically affecting brain regions implicated inhigher-order visual processing, particularly in the righthemisphere (Fig. 2A). This is further illustrated by over-laying the binarized 18F-AV1451 and 18F-FDG significancemaps (Fig. 2D). Additionally, 18F-AV1451 uptake was ele-vated in several brain regions where 18F-FDG uptake didnot differ from controls, including primary visual cortexand posterior cortex in the left hemisphere. Contraryto the regional specificity of 18F-AV1451 and 18F-FDG,11C-PiB retention was distributed throughout the neocor-tex and implicated both clinically affected and relativelyspared regions (e.g. extensive binding in frontal cortex;Fig. 2A).

In line with the clinical presentation, the 18F-AV1451 pat-tern in patients with an amnestic-predominant presentationmost prominently affected the medial temporal lobes and lat-eral temporoparietal cortex (Fig. 2B). When assessing theparametric images and AIs of the five logopenic variantPPA cases individually, three patients showed the predictedleft4 right asymmetry, one was fairly symmetric, and oneshowed right4 left 18F-AV1451 uptake (Table 2 andFig. 2E). Notably, the two patients with most advanced dis-ease severity showed the greatest 18F-AV1451 uptake in theright hemisphere and in anterior brain regions. On group-levelvoxelwise analyses, the 18F-AV1451 pattern in patients withlogopenic variant PPA was rather symmetric, with uptakemainly observed in bilateral temporoparietal regions that aretypically involved in language function (Fig. 2C). Voxelwise11C-PiB and 18F-FDG contrasts between amnestic Alzheimer’sdisease and logopenic variant PPA patients against controlsare shown in Supplementary Fig. 3. In general, the results aresimilar to those seen in patients with PCA (i.e. widespreadneocortical 11C-PiB binding, while 18F-FDG uptake is moreregion-specific), but should be interpreted with caution giventhe smaller sample size due to missing scans.

Figure 1 18F-AV1451 uptake in individuals with distinct phenotypes of Alzheimer’s disease. SUVR 18F-AV1451 images (neurological

orientation) in (A) a 59-year-old female (MMSE: 28) with posterior cortical atrophy [note that this a different patient than presented in

Ossenkoppele et al. (2015d)]; (B) a 77-year-old female (MMSE: 17) with logopenic variant PPA; (C) a 71-year-old female (MMSE: 23) with amnestic

Alzheimer’s disease; (D) a 59-year-old female (MMSE: 27) with non-amnestic Alzheimer’s disease; (E) a 59-year-old male (MMSE: 21) with a

behavioural presentation of Alzheimer’s disease, and (F) a 60-year-old female (MMSE: 16) with a corticobasal syndrome affecting the left

hemibody.

In vivo tau PET in Alzheimer’s disease BRAIN 2016: 139; 1551–1567 | 1557

by guest on May 23, 2016

http://brain.oxfordjournals.org/D

ownloaded from

Voxelwise contrasts betweenpatients and control subjects

Next, we performed voxelwise contrasts for 18F-AV1451,11C-PiB and 18F-FDG between patients with posterior cor-tical atrophy and controls. In line with our hypothesis anda previous case study (Ossenkoppele et al., 2015d), pa-tients with PCA showed substantial inverse spatial overlapbetween greater 18F-AV1451 and reduced 18F-FDGuptake, specifically affecting brain regions implicated inhigher-order visual processing, particularly in the righthemisphere (Fig. 2A). This is further illustrated by over-laying the binarized 18F-AV1451 and 18F-FDG significancemaps (Fig. 2D). Additionally, 18F-AV1451 uptake was ele-vated in several brain regions where 18F-FDG uptake didnot differ from controls, including primary visual cortexand posterior cortex in the left hemisphere. Contraryto the regional specificity of 18F-AV1451 and 18F-FDG,11C-PiB retention was distributed throughout the neocor-tex and implicated both clinically affected and relativelyspared regions (e.g. extensive binding in frontal cortex;Fig. 2A).

In line with the clinical presentation, the 18F-AV1451 pat-tern in patients with an amnestic-predominant presentationmost prominently affected the medial temporal lobes and lat-eral temporoparietal cortex (Fig. 2B). When assessing theparametric images and AIs of the five logopenic variantPPA cases individually, three patients showed the predictedleft4 right asymmetry, one was fairly symmetric, and oneshowed right4 left 18F-AV1451 uptake (Table 2 andFig. 2E). Notably, the two patients with most advanced dis-ease severity showed the greatest 18F-AV1451 uptake in theright hemisphere and in anterior brain regions. On group-levelvoxelwise analyses, the 18F-AV1451 pattern in patients withlogopenic variant PPA was rather symmetric, with uptakemainly observed in bilateral temporoparietal regions that aretypically involved in language function (Fig. 2C). Voxelwise11C-PiB and 18F-FDG contrasts between amnestic Alzheimer’sdisease and logopenic variant PPA patients against controlsare shown in Supplementary Fig. 3. In general, the results aresimilar to those seen in patients with PCA (i.e. widespreadneocortical 11C-PiB binding, while 18F-FDG uptake is moreregion-specific), but should be interpreted with caution giventhe smaller sample size due to missing scans.

Figure 1 18F-AV1451 uptake in individuals with distinct phenotypes of Alzheimer’s disease. SUVR 18F-AV1451 images (neurological

orientation) in (A) a 59-year-old female (MMSE: 28) with posterior cortical atrophy [note that this a different patient than presented in

Ossenkoppele et al. (2015d)]; (B) a 77-year-old female (MMSE: 17) with logopenic variant PPA; (C) a 71-year-old female (MMSE: 23) with amnestic

Alzheimer’s disease; (D) a 59-year-old female (MMSE: 27) with non-amnestic Alzheimer’s disease; (E) a 59-year-old male (MMSE: 21) with a

behavioural presentation of Alzheimer’s disease, and (F) a 60-year-old female (MMSE: 16) with a corticobasal syndrome affecting the left

hemibody.

In vivo tau PET in Alzheimer’s disease BRAIN 2016: 139; 1551–1567 | 1557

by guest on May 23, 2016

http://brain.oxfordjournals.org/D

ownloaded from

Amyloid Risk Score

80% träffsäkerhetMinnestest, blodprov (APOE-genotyp), ålder

Faser i läkemedelsstudier

Ett årtionde av misslyckandeMellan 2002–2012

413 alzheimerstudier (124 fas 1, 206 fase 2, 83 fase 3)

agents, especially in Phase 3. In Phase 2, the mean numberof patients was 199.7 for symptomatic cognitive-enhancingagents, 119.5 for symptomatic behavior agents, 162.61for disease-modifying small molecules (P = 0.28 comparedwith cognitive enhancer), 102 for immunotherapies(P < 0.001 compared with cognitive enhancer), 32.13 fordevices, and 20 for stem cells.The mean number or patients included in Phase 3

trials was 313.8 for symptomatic cognitive-enhancingagents, 215.3 for symptomatic behavior agents, 1,086.0

for disease-modifying small molecules (P < 0.0001 comparedwith cognitive enhancer), 1,321.9 for immunotherapies(P = 0.068 compared with cognitive enhancer), and 178.5for devices. In all categories, fewer patients were includedin Phase 2 than in Phase 3 trials.We examined the progression of compounds from Phase

1 to Phase 2 and from Phase 2 to Phase 3. We reviewedthe percentage of compounds that appeared in Phase 1and were advanced to Phase 2 and the percentage thatwere listed in Phase 2 and then advanced to Phase 3.Twenty-one compounds that were registered in Phase 1during the 2002 through 2012 period were also tested inPhase 2 (28% advance rate; 72% attrition rate). Fourteencompounds registered in Phase 2 were advanced to Phase3 and tested during the decade reviewed (8% advance rate;92% attrition rate). During the decade reviewed, onecompound (memantine) was advanced from Phase 3 to theFDA for review and approval, and 54 compounds weretested in Phase 3 during this period (1.8% advance rate;98.2% attrition rate; for this calculation, we excluded allcurrent Phase 3 compounds because they may succeed inadvancing to the FDA for review). Overall, 244 compoundswere assessed in the decade of 2002 through 2012 and onewas approved for marketing; excluding the 14 compoundscurrently in Phase 3, the success rate for advancing agentsfor regulatory approval is 0.4% (99.6% attrition).We examined the currently active pipeline of AD ther-

apies to understand the characteristics of agents currentlyin development (end date as February 28, 2014). Of these,

Figure 1 Comparison of number of trials of symptomatic cognitive-enhancing agents and of disease-modifying agents in the 2002through 2012 period.

Table 3 Mechanisms of action of drugs currently in Phase 1,Phase 2, and Phase 3 clinical trials (as of February 27, 2014)Unique compounds per MoA(current pipeline 02–27)

Phase 1 Phase 2 Phase 3 Total

Symptomatic for cognition 5 10 10 25

Symptomatic for behavior 2 3 4 9

Disease-modifying smallmolecule (amyloid-related)

4 5 1 10

Disease-modifying smallmolecule (tau-related)

3 0 1 4

Disease-modifying smallmolecule (neuroprotector)

2 19 4 25

Disease-modifyingimmunotherapy

4 8 3 15

Therapeutic device 2 4 0 6

Stem cells 0 1 0 1

Total 22 50 23 95

Cummings et al. Alzheimer's Research & Therapy Page 4 of 72014, 6:37http://alzres.com/content/6/4/37 0.4% success rate

En blev godkänd efter fas 3 (memantine)

Aducanumab

• En naturlig, mänsklig antikropp

• Binder in till alla beta-amyloidformer i hjärnan

165 patienter med alzheimer(prodromal eller lindrig)

Resultat på amyloid PET

ARTICLE RESEARCH

1 S E P T E M B E R 2 0 1 6 | V O L 5 3 7 | N A T U R E | 5 1

were similar in patients with mild and prodromal AD, and apolipopro-tein E (ApoE) ε4 carriers and non-carriers (Extended Data Fig. 2a, b). Pre-specified regional analyses of SUVR changes demonstrated sta-tistically significant dose-dependent reductions in all brain regions, except for the pons and sub-cortical white matter, two areas in which Aβ plaques are not expected to accumulate (Extended Data Fig. 3).

Effect on clinical measuresClinical assessments were exploratory as the study was not powered to detect clinical change. The test of dose response was the pre-specified primary analysis for the clinical assessments. Analysis of change from baseline on the CDR-SB (adjusted for baseline CDR-SB and ApoE ε4 status) demonstrated dose-dependent slowing of clinical progression with aducanumab treatment at one year (dose-response, P < 0.05), with the greatest slowing for 10 mg kg−1 (P < 0.05 versus placebo) (Fig. 3a, Extended Data Table 1). Sensitivity analysis using a mixed model for repeated measures (MMRM) also showed a trend for slowing of decline on the CDR-SB at one year (P = 0.07 with 10 mg kg−1 aducanumab versus placebo). A dose-dependent slowing of clinical progression on the Mini Mental State Examination (MMSE) with aducanumab treatment was also observed at one year (dose-response, P < 0.05), with the greatest effects at 3 and 10 mg kg−1 aducanumab (P < 0.05 versus placebo) (Fig. 3b, Extended Data Table 1). On sensitivity anal-ysis using MMRM, the greatest difference was retained for 10 mg kg−1 aducanumab (P < 0.05 versus placebo), with a smaller difference at 3 mg kg−1 (P = 0.10 versus placebo). No changes from baseline after one year were found on the composite neuropsychological test battery (NTB) or the Free and Cued Selective Reminding Test (FCSRT) free recall (Extended Data Table 1), but skewed non-normal (floor) effects at baseline were observed. The floor effects on the NTB were seen in the individual tests; specifically, in the two most clinically relevant com-ponents given the stage of the population enrolled: Wechsler Memory Scale-Fourth Edition Verbal Paired Associates II (WMS-IV VPA II) and Rey Auditory Verbal Learning Test (RAVLT) delayed recall of the NTB memory domain.

Safety and tolerabilityThe most common adverse effects were amyloid-related imaging abnormalities (ARIA), headache, urinary tract infection, and upper respiratory tract infection (Table 2). Using the most specific descrip-

tion of ARIA by magnetic resonance imaging (MRI), ARIA-vasogenic oedema (ARIA-E) abnormalities occurred in no patients receiving placebo compared with 1 (3%), 2 (6%), 11 (37%), and 13 (41%) patients receiving 1, 3, 6 and 10 mg kg−1 aducanumab, respectively (Extended Data Table 2). ARIA-E was generally observed early in the course of treatment, MRI findings typically resolved within 4–12 weeks, and of the 27 patients who developed ARIA-E, 15 (56%) continued treatment (Supplementary Information). All cases of symptomatic ARIA were

Table 1 | Baseline characteristics

Aducanumab

Characteristic Placebo (n = 40) 1 mg kg−1 (n = 31) 3 mg kg−1 (n = 32) 6 mg kg−1 (n = 30) 10 mg kg−1 (n = 32) Total (n = 165)*

Years of age (mean ± s.d.) 72.8 ± 7.2 72.6 ± 7.8 70.5 ± 8.2 73.3 ± 9.3 73.7 ± 8.3 72.6 ± 8.1

Female sex (n (%)) 23 (58) 13 (42) 17 (53) 15 (50) 15 (47) 83 (50)

ApoE ε4 (n (%)) Carriers 26 (65) 19 (61) 21 (66) 21 (70) 20 (63) 107 (65)

Non-carriers 14 (35) 12 (39) 11 (34) 9 (30) 12 (38) 58 (35)

Clinical stage (n (%)) Prodromal 19 (48) 10 (32) 14 (44) 12 (40) 13 (41) 68 (41)

Mild 21 (53) 21 (68) 18 (56) 18 (60) 19 (59) 97 (59)

MMSE (mean ± s.d.) 24.7 ± 3.6 23.6 ± 3.3 23.2 ± 4.2 24.4 ± 2.9 24.8 ± 3.1 24.2 ± 3.5

Global CDR (n (%)) 0.5 34 (85) 22 (71) 22 (69) 25 (83) 24 (75) 127 (77)

1 6 (15) 9 (29) 10 (31) 5 (17) 8 (25) 38 (23)

CDR-SB (mean ± s.d.) 2.66 ± 1.50 3.40 ± 1.76 3.50 ± 2.06 3.32 ± 1.54 3.14 ± 1.71 3.18 ± 1.72

FCSRT sum of free recall score (mean ± s.d.)

15.2 ± 8.5 13.2 ± 9.0 13.8 ± 8.0 14.4 ± 8.3 14.6 ± 8.3 14.3 ± 8.3

PET SUVR composite score (mean ± s.d.)

1.44 ± 0.17 1.44 ± 0.15 1.46 ± 0.15 1.43 ± 0.20 1.44 ± 0.19 1.44 ± 0.17

AD medications use† (n (%))

24 (60) 19 (61) 28 (88) 20 (67) 17 (53) 108 (65)

Percentages are rounded to the nearest integer. AD, Alzheimer’s disease; ApoE ε4, apolipoprotein E ε4 allele; CDR, Clinical Dementia Rating; CDR-SB, Clinical Dementia Rating—Sum of Boxes; FCSRT, Free and Cued Selective Reminding Test; MMSE, Mini-Mental State Examination; PET, positron emission tomography; SD, standard deviation; SUVR, standard uptake value ratio.*Number of patients dosed. †Cholinesterase inhibitors and/or memantine.

Placebo

Baseline One year

3 mg kg–1

6 mg kg–1

10 mg kg–1

Figure 1 | Amyloid plaque reduction with aducanumab: example amyloid PET images at baseline and week 54. Individuals were chosen based on visual impression and SUVR change relative to average one-year response for each treatment group (n = 40, 32, 30 and 32, respectively). Axial slice shows anatomical regions in posterior brain putatively related to AD pathology. SUVR, standard uptake value ratio.

© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Före behandling

Efter behandling

Ökande dos

Placebo

KOGNITIVA MÅTTKLINISK BEDÖMNING (CDR)ARTICLERESEARCH

5 2 | N A T U R E | V O L 5 3 7 | 1 S E P T E M B E R 2 0 1 6

required to be reported as medically important serious adverse effects. No patients were hospitalised for ARIA. The only serious adverse effects (by preferred term) that occurred in more than one patient in any treatment group were ARIA (0, 1 (3%), 1 (3%), 4 (13%), and 5 (16%) of patients receiving placebo, and 1, 3, 6 and 10 mg kg−1 aducanumab, respectively) and superficial siderosis of the central nervous system (0, 1 (3%), 0, 2 (7%), and 3 (9%) of patients receiving placebo and 1, 3, 6 and 10 mg kg−1 aducanumab, respectively). Owing to the require-ment for repeated MRI assessments of those patients who developed ARIA, these individuals were partially unblinded to treatment. Other adverse effects and serious adverse effects were consistent with the patient population. There were no drug-related deaths (Supplementary Information).

PharmacokineticsThe pharmacokinetics of aducanumab (maximum concentration (Cmax) and cumulative area under the concentration curve (AUC)) were linear across the dose range in patients who received all 14 planned doses (Extended Data Table 3). The median plasma half-life was 21 days. In total, 3 of 118 evaluable patients (3%) in the combined aducanumab groups developed treatment-emergent anti-aducanumab antibodies within the first year of treatment. Antibody responses were

transient, with minimal titres, and had no apparent effect on adu-canumab pharmacokinetics or safety.

Brain penetration and binding to Aβ plaquesIn the preclinical studies which preceded PRIME, systemically admin-istered aducanumab (single dose, 30 mg kg−1 intraperitoneally (i.p.)) bound to diffuse and compact Aβ plaques in the brains of 22-month-old female Tg2576 transgenic mice (‘Target engagement study’; Extended Data Fig. 4a–d). Cmax in plasma was 181 µg ml−1, with a terminal elimination half-life (t1/2) of 2.5 days. The Cmax in brain was 1,062 ng g−1 of tissue, and approximately 400–500 ng g−1 of drug was measured 3 weeks after dosing, suggesting long-term retention. Consequently, the brain:plasma AUC ratio of 1.3% was higher than the 0.1% frequently reported for systemically administered antibodies11,12.

Administration of a single dose of aducanumab did not affect plasma (Extended Data Fig. 4b) or brain (data not shown) Aβ concentrations, consistent with the observation that aducanumab does not bind to soluble Aβ monomers. In contrast, the murine bapineuzumab precur-sor antibody 3D6, which binds to Aβ monomers, triggered a transient plasma Aβ spike (Extended Data Fig. 4b). Similarly, plasma Aβ con-centrations were stable after repeated dosing with aducanumab in the PRIME study (data not shown). Within 24 h of dosing, aducanumab bound to parenchymal brain Aβ with a spatial pattern essentially superimposable with ex vivo pan-Aβ antibody staining, confirming that aducanumab binds all morphological types of brain Aβ plaques in vivo, including diffuse Aβ deposits and compact Aβ plaques (Extended Data Fig. 4c, d). Aducanumab binding to Aβ deposited in cerebral amy-loid angiopathy (CAA) lesions within brain blood vessel walls was less

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Figure 2 | Amyloid plaque reduction with aducanumab. a–c, Change from baseline (a, analyses using ANCOVA), SUVR values (b), and categorization of change in amyloid PET (c) at week 54 and associated change from baseline CDR-SB and MMSE in aducanumab-treated patients (post hoc analysis). Categorization of amyloid PET at week 54 based on s.d. of change from baseline in placebo-treated patients. **P < 0.01; ***P < 0.001 versus placebo; two-sided tests with no adjustments for multiple comparisons. Mean ± s.e. ANCOVA, analysis of covariance; CDR-SB, Clinical Dementia Rating—Sum of Boxes; MMSE, Mini Mental State Examination; SUVR, standard uptake value ratio.

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Figure 3 | Aducanumab effect (change from baseline) on CDR-SB and MMSE. a, b, Aducanumab effect on CDR-SB (a) and MMSE (b). *P < 0.05 versus placebo; two-sided tests with no adjustments for multiple comparisons. CDR-SB and MMSE were exploratory endpoints. Adjusted mean ± s.e. Analyses using ANCOVA. CDR-SB, Clinical Dementia Rating—Sum of Boxes; MMSE, Mini Mental State Examination.

© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

KOGNITIVA MÅTTMMT

ARTICLERESEARCH

5 2 | N A T U R E | V O L 5 3 7 | 1 S E P T E M B E R 2 0 1 6

required to be reported as medically important serious adverse effects. No patients were hospitalised for ARIA. The only serious adverse effects (by preferred term) that occurred in more than one patient in any treatment group were ARIA (0, 1 (3%), 1 (3%), 4 (13%), and 5 (16%) of patients receiving placebo, and 1, 3, 6 and 10 mg kg−1 aducanumab, respectively) and superficial siderosis of the central nervous system (0, 1 (3%), 0, 2 (7%), and 3 (9%) of patients receiving placebo and 1, 3, 6 and 10 mg kg−1 aducanumab, respectively). Owing to the require-ment for repeated MRI assessments of those patients who developed ARIA, these individuals were partially unblinded to treatment. Other adverse effects and serious adverse effects were consistent with the patient population. There were no drug-related deaths (Supplementary Information).

PharmacokineticsThe pharmacokinetics of aducanumab (maximum concentration (Cmax) and cumulative area under the concentration curve (AUC)) were linear across the dose range in patients who received all 14 planned doses (Extended Data Table 3). The median plasma half-life was 21 days. In total, 3 of 118 evaluable patients (3%) in the combined aducanumab groups developed treatment-emergent anti-aducanumab antibodies within the first year of treatment. Antibody responses were

transient, with minimal titres, and had no apparent effect on adu-canumab pharmacokinetics or safety.

Brain penetration and binding to Aβ plaquesIn the preclinical studies which preceded PRIME, systemically admin-istered aducanumab (single dose, 30 mg kg−1 intraperitoneally (i.p.)) bound to diffuse and compact Aβ plaques in the brains of 22-month-old female Tg2576 transgenic mice (‘Target engagement study’; Extended Data Fig. 4a–d). Cmax in plasma was 181 µg ml−1, with a terminal elimination half-life (t1/2) of 2.5 days. The Cmax in brain was 1,062 ng g−1 of tissue, and approximately 400–500 ng g−1 of drug was measured 3 weeks after dosing, suggesting long-term retention. Consequently, the brain:plasma AUC ratio of 1.3% was higher than the 0.1% frequently reported for systemically administered antibodies11,12.

Administration of a single dose of aducanumab did not affect plasma (Extended Data Fig. 4b) or brain (data not shown) Aβ concentrations, consistent with the observation that aducanumab does not bind to soluble Aβ monomers. In contrast, the murine bapineuzumab precur-sor antibody 3D6, which binds to Aβ monomers, triggered a transient plasma Aβ spike (Extended Data Fig. 4b). Similarly, plasma Aβ con-centrations were stable after repeated dosing with aducanumab in the PRIME study (data not shown). Within 24 h of dosing, aducanumab bound to parenchymal brain Aβ with a spatial pattern essentially superimposable with ex vivo pan-Aβ antibody staining, confirming that aducanumab binds all morphological types of brain Aβ plaques in vivo, including diffuse Aβ deposits and compact Aβ plaques (Extended Data Fig. 4c, d). Aducanumab binding to Aβ deposited in cerebral amy-loid angiopathy (CAA) lesions within brain blood vessel walls was less

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Figure 2 | Amyloid plaque reduction with aducanumab. a–c, Change from baseline (a, analyses using ANCOVA), SUVR values (b), and categorization of change in amyloid PET (c) at week 54 and associated change from baseline CDR-SB and MMSE in aducanumab-treated patients (post hoc analysis). Categorization of amyloid PET at week 54 based on s.d. of change from baseline in placebo-treated patients. **P < 0.01; ***P < 0.001 versus placebo; two-sided tests with no adjustments for multiple comparisons. Mean ± s.e. ANCOVA, analysis of covariance; CDR-SB, Clinical Dementia Rating—Sum of Boxes; MMSE, Mini Mental State Examination; SUVR, standard uptake value ratio.

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Figure 3 | Aducanumab effect (change from baseline) on CDR-SB and MMSE. a, b, Aducanumab effect on CDR-SB (a) and MMSE (b). *P < 0.05 versus placebo; two-sided tests with no adjustments for multiple comparisons. CDR-SB and MMSE were exploratory endpoints. Adjusted mean ± s.e. Analyses using ANCOVA. CDR-SB, Clinical Dementia Rating—Sum of Boxes; MMSE, Mini Mental State Examination.

© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

BACE-hämmaren verubecestat

Bakgrund

• Försöksdjur utan BACE/beta-secretas: Amyloid försvinner och kognition förbättras

• Människor med BACE-mutation:85% minskad risk att få alzheimer

EFFEKT HOS FRISKA ÄLDRE

tended to be lower in AD patients relative to healthy subjects. This wasespecially true for Ab42, where this variation between healthy subjectsand AD patients (0.91 versus 0.96) was associated with nonoverlapping95% confidence intervals, which is suggestive of a real difference.

Because the model included integrated variability terms that wereinformed by all subjects enrolled across the three phase 1 studies,model-based simulations are informative of the likely response dis-tribution despite the small size of each dose group in the phase 1 studies.Consistent with the observed reduction of CSF Ab40 in AD patients(Fig. 6), model-based prediction of the verubecestat dose-response re-lationship (Fig. 7A) and distribution of individual responses (Fig. 7B)indicated that 12 mg daily would produce partial reduction in CSFAb40 (96.6% of AD patients with CSF Ab40 reduction of 50 to 75%;average reduction, 67.1%), whereas 40 mg daily would produce near-maximal CSF Ab40 reduction that is meaningfully different from 12 mg(94.6% of AD patients with CSF Ab40 reduction of 80 to 90%; averagereduction, 83.7%). The model predicts a slightly greater reduction ofde novo brainAb40 production relative to CSFAb40 reduction at thesetwo doses (average reductions of 72.2 and 90.1% at the 12- and 40-mgdoses, respectively; Fig. 7B).

DISCUSSIONDespite the large body of evidence supporting the amyloid hypothesis ofAD pathogenesis, efforts to develop agents that safely and unambigu-ously reduce CNS concentrations of Ab in humans have not been suc-cessful to date. Although this lack of success has been cited as evidenceagainst the amyloid hypothesis, the treatments evaluated to date havelacked convincing evidence of substantial and sustainedCNSAb reduc-tion at doses having an acceptable tolerability profile (2, 24). Given therequired role of BACE1 inAb production, inhibition of this enzyme haslong been viewed as a promising Ab-lowering therapeutic target, butseveral obstacles have prevented BACE1 inhibitors from advancing topivotal clinical trials (3, 12).Our efforts to developpotent, selective, orallybioavailable BACE1 inhibitors that safely reduce Ab in the CNS culmi-nated in the discovery of verubecestat (13). Verubecestat inhibits BACE1with similar potency in a purified enzyme assay and in intact cells. Thissuggests that the compound can traverse the multiple membranes re-quired to access BACE1 in cells, consistent with its high permeability.Verubecestat also proved to be a potent and effective inhibitor of plasma,CSF, and cortical Ab40, Ab42, and sAPPb production in both rats andmonkeys, achieving >90% reduction in all three compartments. Its ability

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Fig. 4. Oral administration of verubecestat to healthy nonelderly adults.Subjects with indwelling lumbar catheters in the intrathecal space were orallyadministered placebo or single doses of 20, 100, or 550 mg of verubecestat.CSF and blood samples were obtained before dosing and every 2 hours for36 hours after dosing via lumbar puncture or via indwelling catheters. Singledoses of verubecestat reduced CSF Ab40 (A), Ab42 (B), and sAPPb (C). CSFAb1–40, Ab1–42, and sAPPb were quantified using validated Meso ScaleDiagnostics Ultra-sensitive immunoassays. Values for CSF Ab40, Ab42, andsAPPb are expressed as a percent relative to baseline and are means ± SEMfrom five to six subjects per group. Plasma and CSF concentrations of veru-becestat from this study are shown in table S9.

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tended to be lower in AD patients relative to healthy subjects. This wasespecially true for Ab42, where this variation between healthy subjectsand AD patients (0.91 versus 0.96) was associated with nonoverlapping95% confidence intervals, which is suggestive of a real difference.

Because the model included integrated variability terms that wereinformed by all subjects enrolled across the three phase 1 studies,model-based simulations are informative of the likely response dis-tribution despite the small size of each dose group in the phase 1 studies.Consistent with the observed reduction of CSF Ab40 in AD patients(Fig. 6), model-based prediction of the verubecestat dose-response re-lationship (Fig. 7A) and distribution of individual responses (Fig. 7B)indicated that 12 mg daily would produce partial reduction in CSFAb40 (96.6% of AD patients with CSF Ab40 reduction of 50 to 75%;average reduction, 67.1%), whereas 40 mg daily would produce near-maximal CSF Ab40 reduction that is meaningfully different from 12 mg(94.6% of AD patients with CSF Ab40 reduction of 80 to 90%; averagereduction, 83.7%). The model predicts a slightly greater reduction ofde novo brainAb40 production relative to CSFAb40 reduction at thesetwo doses (average reductions of 72.2 and 90.1% at the 12- and 40-mgdoses, respectively; Fig. 7B).

DISCUSSIONDespite the large body of evidence supporting the amyloid hypothesis ofAD pathogenesis, efforts to develop agents that safely and unambigu-ously reduce CNS concentrations of Ab in humans have not been suc-cessful to date. Although this lack of success has been cited as evidenceagainst the amyloid hypothesis, the treatments evaluated to date havelacked convincing evidence of substantial and sustainedCNSAb reduc-tion at doses having an acceptable tolerability profile (2, 24). Given therequired role of BACE1 inAb production, inhibition of this enzyme haslong been viewed as a promising Ab-lowering therapeutic target, butseveral obstacles have prevented BACE1 inhibitors from advancing topivotal clinical trials (3, 12).Our efforts to developpotent, selective, orallybioavailable BACE1 inhibitors that safely reduce Ab in the CNS culmi-nated in the discovery of verubecestat (13). Verubecestat inhibits BACE1with similar potency in a purified enzyme assay and in intact cells. Thissuggests that the compound can traverse the multiple membranes re-quired to access BACE1 in cells, consistent with its high permeability.Verubecestat also proved to be a potent and effective inhibitor of plasma,CSF, and cortical Ab40, Ab42, and sAPPb production in both rats andmonkeys, achieving >90% reduction in all three compartments. Its ability

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Fig. 4. Oral administration of verubecestat to healthy nonelderly adults.Subjects with indwelling lumbar catheters in the intrathecal space were orallyadministered placebo or single doses of 20, 100, or 550 mg of verubecestat.CSF and blood samples were obtained before dosing and every 2 hours for36 hours after dosing via lumbar puncture or via indwelling catheters. Singledoses of verubecestat reduced CSF Ab40 (A), Ab42 (B), and sAPPb (C). CSFAb1–40, Ab1–42, and sAPPb were quantified using validated Meso ScaleDiagnostics Ultra-sensitive immunoassays. Values for CSF Ab40, Ab42, andsAPPb are expressed as a percent relative to baseline and are means ± SEMfrom five to six subjects per group. Plasma and CSF concentrations of veru-becestat from this study are shown in table S9.

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to reduce CSF and brain concentrations of Ab40, Ab42, and sAPPb inanimals was maintained after chronic treatment, indicating that no com-pensatory biological processes overcome the effects of BACE1 inhibition.Verubecestat was substantially more potent in reducing plasma Ab40than in reducing CSF or brain Ab40, at least in part, because verubecestatis a substrate of P-glycoprotein, which transports compounds out of thebrain (see below).

Administration of both single and multiple doses of verubecestat tohealthy adult volunteers reduced plasma and CSF levels of Ab40, Ab42,and sAPPb in a dose-dependentmanner, with the highest doses achiev-ing≥90% reduction. The potency andmaximal effect of verubecestat toreduce plasma andCSF concentrations of Ab40, Ab42, and sAPPbweresimilar in humans and animals, and the observed human t1/2, dose, andplasma Cmax and AUC required to achieve the targeted reduction of CSFAb40 were also similar to the predictions derived from animal studies.This concordance highlights the value of measuring identical end pointsin animal and human studies, a practice that should greatly improve thehistorically poor clinical translation in neuroscience drug development

programs. As in the in vitro and animal studies, the potencies and max-imal effects of verubecestat in reducing CSF Ab40, Ab42, and sAPPb inhumans were comparable, and the degrees of reduction were highlycorrelated. Furthermore, the PK/PD modeling suggested that verubece-stat effects on all three APP metabolites could be interpreted via a singledrug action, that is, BACE1 inhibition in the brain. Therefore, these datasuggest that measurement of any one of these three APPmetabolites is asuitable surrogate for assessment of BACE1 inhibition in humans. Theability of themodel to interpret thedata basedonBACE1 inhibition alonesuggests that a substrate (APP) does not accumulate in humans afterBACE1 inhibition, probably because of compensatory metabolism byotherpathways [for example, thea-secretasepathwayor themore recentlydescribedh-secretase pathway (25, 26)]. This is in contrast to g-secretaseinhibition where the potentially neurotoxic substrate C99 accumulatessubstantially [for example, (27)]. Although verubecestat is a P-glycoproteinsubstrate, its potency andmaximal effect in lowering CSF and brain Aband sAPPb were very similar in animals and were achieved at submi-cromolar total plasma concentrations. Furthermore, PK/PD modeling

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Fig. 5. Oral administration of multiple doses of verubecestat to healthy none-lderly adults. Subjects with indwelling lumbar catheters in the intrathecal spacewere given once-daily oral doses of placebo or verubecestat at 10, 40, 150, or250 mg for 14 days. CSF and blood samples were obtained the day before dosingvia lumbar puncture (baseline) and every 2 hours for 36 hours after dosing on day 14via indwelling catheters. Multiple doses of verubecestat reduced CSF Ab40 (A), Ab42(B), and sAPPb (C). Values for CSF Ab40, Ab42, and sAPPb are expressed as a percentrelative to baseline and are means ± SEM from 3 to 10 subjects per group. CSF Ab1–40, Ab1–42, and sAPPbwere quantified using validatedMeso Scale Diagnostics Ultra-sensitive immunoassays. Plasma and CSF concentrations of verubecestat from thisstudy are shown in table S10.

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to reduce CSF and brain concentrations of Ab40, Ab42, and sAPPb inanimals was maintained after chronic treatment, indicating that no com-pensatory biological processes overcome the effects of BACE1 inhibition.Verubecestat was substantially more potent in reducing plasma Ab40than in reducing CSF or brain Ab40, at least in part, because verubecestatis a substrate of P-glycoprotein, which transports compounds out of thebrain (see below).

Administration of both single and multiple doses of verubecestat tohealthy adult volunteers reduced plasma and CSF levels of Ab40, Ab42,and sAPPb in a dose-dependentmanner, with the highest doses achiev-ing≥90% reduction. The potency andmaximal effect of verubecestat toreduce plasma andCSF concentrations of Ab40, Ab42, and sAPPbweresimilar in humans and animals, and the observed human t1/2, dose, andplasma Cmax and AUC required to achieve the targeted reduction of CSFAb40 were also similar to the predictions derived from animal studies.This concordance highlights the value of measuring identical end pointsin animal and human studies, a practice that should greatly improve thehistorically poor clinical translation in neuroscience drug development

programs. As in the in vitro and animal studies, the potencies and max-imal effects of verubecestat in reducing CSF Ab40, Ab42, and sAPPb inhumans were comparable, and the degrees of reduction were highlycorrelated. Furthermore, the PK/PD modeling suggested that verubece-stat effects on all three APP metabolites could be interpreted via a singledrug action, that is, BACE1 inhibition in the brain. Therefore, these datasuggest that measurement of any one of these three APPmetabolites is asuitable surrogate for assessment of BACE1 inhibition in humans. Theability of themodel to interpret thedata basedonBACE1 inhibition alonesuggests that a substrate (APP) does not accumulate in humans afterBACE1 inhibition, probably because of compensatory metabolism byotherpathways [for example, thea-secretasepathwayor themore recentlydescribedh-secretase pathway (25, 26)]. This is in contrast to g-secretaseinhibition where the potentially neurotoxic substrate C99 accumulatessubstantially [for example, (27)]. Although verubecestat is a P-glycoproteinsubstrate, its potency andmaximal effect in lowering CSF and brain Aband sAPPb were very similar in animals and were achieved at submi-cromolar total plasma concentrations. Furthermore, PK/PD modeling

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Fig. 5. Oral administration of multiple doses of verubecestat to healthy none-lderly adults. Subjects with indwelling lumbar catheters in the intrathecal spacewere given once-daily oral doses of placebo or verubecestat at 10, 40, 150, or250 mg for 14 days. CSF and blood samples were obtained the day before dosingvia lumbar puncture (baseline) and every 2 hours for 36 hours after dosing on day 14via indwelling catheters. Multiple doses of verubecestat reduced CSF Ab40 (A), Ab42(B), and sAPPb (C). Values for CSF Ab40, Ab42, and sAPPb are expressed as a percentrelative to baseline and are means ± SEM from 3 to 10 subjects per group. CSF Ab1–40, Ab1–42, and sAPPbwere quantified using validatedMeso Scale Diagnostics Ultra-sensitive immunoassays. Plasma and CSF concentrations of verubecestat from thisstudy are shown in table S10.

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EFFEKT HOS ALZHEIMERPATIENTER

of the human data suggests that verubecestat has comparable abilityto reduce de novo brain production and CSF levels of Ab40, Ab42,and sAPPb. These data suggest that high BACE1 affinity and highpermeability of verubecestat can overcome CNS efflux mediated byP-glycoprotein and that measurement of CSF Ab40, Ab42, and sAPPbis a reasonable surrogate for verubecestat effects on brain concentra-tions of these APP metabolites in humans. At doses of ≥20 to 40 mg,reduction of CSF Ab and sAPPb was sustained for at least 24 hoursand unbound trough (C24hr) plasma, and CSF concentrations of ver-ubecestat were at or above the in vitro IC50. Along with the observedhuman t1/2 (14 to 24 hours), these data confirm that verubecestat canbe dosed once per day.

This report also describes testing of BACE inhibition inADpatients,which was considered critical for a number of reasons. Unlike healthyadults, AD patients have a large reservoir of oligomeric, fibrillar, andplaque-borne Ab in the brain, which may contribute to CSF levelsand may be refractory to short-term inhibition of BACE1. BACE1 pro-tein and enzymatic activity are also up-regulated in the brains of AD

patients, particularly around amyloid plaques (28). Finally, AD patientsmay be more susceptible to drug-induced adverse effects than healthysubjects. Overall, the safety and effect of verubecestat on Ab40, Ab42,and sAPPb in CSF were very similar in AD patients and healthy adults.The estimated potency (IC50) of verubecestatwas comparable in healthyadults andADpatients, suggesting that the disease has no impact on theability of verubecestat to inhibit BACE1. The Emax value of CSF Ab42was slightly less in AD subjects than in healthy adults. Because Emax

values represent the contribution of de novoAb42 production, this sug-gests a small (~10%) contribution of dissociation of oligomeric, plaque-derived, or other slowly cleared sources ofAb42 to theCSFAb42 pool inAD patients. Experimental and modeling studies suggest that theseslowly cleared sources of Ab42 may be reduced over time by chronicBACE inhibition (22, 25).

Many previously studied anti-amyloid mechanisms, most notablyg-secretase inhibitors and anti-Ab antibodies, are associated with seriousside effects that limit the dose that can be administered to humans (5, 24).Several recent publications have described adverse phenotypes of Bace1

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Fig. 6. Oral administration of multiple doses of verubecestat to AD patients. ADpatients with indwelling lumbar catheters in the intrathecal space were given once-daily oral doses of placeboor verubecestat at 12, 40, or 60mg for 7 days. CSF andbloodsamples were obtained the day before dosing via lumbar puncture (baseline) and ev-ery 2 hours for 36 hours after dosing on day 7 via indwelling catheters. Multiple dosesof verubecestat reducedCSFAb40 (A), Ab42 (B), and sAPPb (C) after oral administrationto AD patients. Values for CSF Ab40, Ab42, and sAPPb are expressed as a percent re-lative to baseline and are means ± SEM from five to eight subjects per group. Ab1–40,Ab1–42, and sAPPbwere quantified using validatedMeso Scale Diagnostics Ultra-sensitiveimmunoassays. Plasma andCSF concentrations of verubecestat from this study are shownin table S11.

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tended to be lower in AD patients relative to healthy subjects. This wasespecially true for Ab42, where this variation between healthy subjectsand AD patients (0.91 versus 0.96) was associated with nonoverlapping95% confidence intervals, which is suggestive of a real difference.

Because the model included integrated variability terms that wereinformed by all subjects enrolled across the three phase 1 studies,model-based simulations are informative of the likely response dis-tribution despite the small size of each dose group in the phase 1 studies.Consistent with the observed reduction of CSF Ab40 in AD patients(Fig. 6), model-based prediction of the verubecestat dose-response re-lationship (Fig. 7A) and distribution of individual responses (Fig. 7B)indicated that 12 mg daily would produce partial reduction in CSFAb40 (96.6% of AD patients with CSF Ab40 reduction of 50 to 75%;average reduction, 67.1%), whereas 40 mg daily would produce near-maximal CSF Ab40 reduction that is meaningfully different from 12 mg(94.6% of AD patients with CSF Ab40 reduction of 80 to 90%; averagereduction, 83.7%). The model predicts a slightly greater reduction ofde novo brainAb40 production relative to CSFAb40 reduction at thesetwo doses (average reductions of 72.2 and 90.1% at the 12- and 40-mgdoses, respectively; Fig. 7B).

DISCUSSIONDespite the large body of evidence supporting the amyloid hypothesis ofAD pathogenesis, efforts to develop agents that safely and unambigu-ously reduce CNS concentrations of Ab in humans have not been suc-cessful to date. Although this lack of success has been cited as evidenceagainst the amyloid hypothesis, the treatments evaluated to date havelacked convincing evidence of substantial and sustainedCNSAb reduc-tion at doses having an acceptable tolerability profile (2, 24). Given therequired role of BACE1 inAb production, inhibition of this enzyme haslong been viewed as a promising Ab-lowering therapeutic target, butseveral obstacles have prevented BACE1 inhibitors from advancing topivotal clinical trials (3, 12).Our efforts to developpotent, selective, orallybioavailable BACE1 inhibitors that safely reduce Ab in the CNS culmi-nated in the discovery of verubecestat (13). Verubecestat inhibits BACE1with similar potency in a purified enzyme assay and in intact cells. Thissuggests that the compound can traverse the multiple membranes re-quired to access BACE1 in cells, consistent with its high permeability.Verubecestat also proved to be a potent and effective inhibitor of plasma,CSF, and cortical Ab40, Ab42, and sAPPb production in both rats andmonkeys, achieving >90% reduction in all three compartments. Its ability

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Fig. 4. Oral administration of verubecestat to healthy nonelderly adults.Subjects with indwelling lumbar catheters in the intrathecal space were orallyadministered placebo or single doses of 20, 100, or 550 mg of verubecestat.CSF and blood samples were obtained before dosing and every 2 hours for36 hours after dosing via lumbar puncture or via indwelling catheters. Singledoses of verubecestat reduced CSF Ab40 (A), Ab42 (B), and sAPPb (C). CSFAb1–40, Ab1–42, and sAPPb were quantified using validated Meso ScaleDiagnostics Ultra-sensitive immunoassays. Values for CSF Ab40, Ab42, andsAPPb are expressed as a percent relative to baseline and are means ± SEMfrom five to six subjects per group. Plasma and CSF concentrations of veru-becestat from this study are shown in table S9.

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Framtida utredning och diagnostik

1.Fånga upp tidigt i primärvården

2.Riskbedömning (kognitivt test, blodprov)

3.Verifiera amyloid-status och ev annan patologi på minnesklinik (LP/PET)

4.Behandling

Framtida behandlingsmodell

• Amyloidpositiv med kognitiv svikt: -Startbehandling (1 års antikroppsbehandling för att ta bort amyloida plack)-Sekundärprofylax (kontinuerlig behandling med BACE-hämmare för att minska produktion)

• Medelålders amyloidpositiv utan symptom:Primärprofylax (kontinuerlig behandling med BACE-hämmare för att minska produktion)

Om sjukdomen fördröjs...Drabbas inte Drabbas

...med 5 år ...med 10 år

Tack!