The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease

Journal name:
Nature
Volume:
537,
Pages:
50–56
Date published:
DOI:
doi:10.1038/nature19323
Received
Accepted
Published online

Abstract

Alzheimer’s disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating—Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

At a glance

Figures

  1. Amyloid plaque reduction with aducanumab: example amyloid PET images at baseline and week 54.
    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.

  2. Amyloid plaque reduction with aducanumab.
    Figure 2: Amyloid plaque reduction with aducanumab.

    ac, 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.

  3. Aducanumab effect (change from baseline) on CDR-SB and MMSE.
    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.

  4. Reduction of amyloid burden following weekly dosing with chaducanumab in 9.5- to 15.5-month-old Tg2576 transgenic mice.
    Figure 4: Reduction of amyloid burden following weekly dosing with chaducanumab in 9.5- to 15.5-month-old Tg2576 transgenic mice.

    a, b, Aβ40 and Aβ42 levels in soluble DEA (a) and insoluble GuHCl (b) brain fractions. c, d, Total brain Aβ (6E10) and compact amyloid plaques (ThioS) in cortex (c) and hippocampus (d) (mean ± s.e.; n = 20–55; dotted line 50% reduction; *P < 0.05 versus control). eh, ThioS staining of amyloid deposits (e) and Visiopharm software (f) differentiated parenchymal deposits (green) from vascular deposits (red) (representative pictures 10× magnification), and quantified area of vascular amyloid (g, h; mean ± s.e.; n = 20–24).

  5. Aducanumab binds selectively to insoluble fibrillar and soluble oligomeric Aβ aggregates.
    Figure 5: Aducanumab binds selectively to insoluble fibrillar and soluble oligomeric Aβ aggregates.

    a, Binding of chaducanumab or 3D6 to immobilized fibrillar Aβ42. Mean ± s.d., in triplicate. b, Capture of soluble monomeric Aβ40 with immobilized chaducanumab or 3D6. Mean ± s.d., in triplicate. c, Dot blots of Aβ42 monomer, soluble oligomers, or insoluble fibrils immunoprecipitated with chaducanumab, 3D6, or irrelevant antibody control. Equivalent concentrations confirmed by direct dot blotting (Peptide). d, e, Immunostaining of Aβ in autopsy brain tissue from a patient with AD with chaducanumab (0.2 μg ml−1) (d) and 22-month-old Tg2576 transgenic mouse brain tissue with aducanumab (60 ng ml−1) (e).

  6. Participant accounting.
    Extended Data Fig. 1: Participant accounting.

    PET, positron emission tomography.

  7. Amyloid plaque reduction with aducanumab by baseline clinical stage and baseline ApoE ε4 status.
    Extended Data Fig. 2: Amyloid plaque reduction with aducanumab by baseline clinical stage and baseline ApoE ε4 status.

    a, b, Analyses by baseline clinical stage were performed using ANCOVA for change from baseline with factors of: treatment, ApoE ε4 status (carrier and non-carrier) and baseline composite SUVR (a), and for analyses by ApoE ε4 status, using treatment and baseline composite SUVR (b). Adjusted mean ± s.e. ApoE ε4, apolipoprotein E ε4 allele; SUVR, standard uptake value ratio.

  8. Amyloid plaque reduction: regional analysis SUVR at week 54.
    Extended Data Fig. 3: Amyloid plaque reduction: regional analysis SUVR at week 54.

    The boxed area indicates the six regions included in the composite score. *P < 0.05; **P < 0.01; ***P < 0.001 versus placebo; two-sided tests with no adjustments for multiple comparisons. Adjusted mean ± s.e. Analyses using ANCOVA. SUVR, standard uptake value ratio.

  9. Brain penetration of aducanumab after a single intraperitoneal administration in 22-month-old Tg2576 transgenic mice.
    Extended Data Fig. 4: Brain penetration of aducanumab after a single intraperitoneal administration in 22-month-old Tg2576 transgenic mice.

    a, b, Aducanumab levels in plasma and brain (a), and plasma Aβ levels after a single dose (b; n = 4–5; mean ± s.e.). c, d, In vivo binding of aducanumab to amyloid deposits detected using a human IgG-specific secondary antibody (c), and ex vivo immunostaining with a pan-Aβ antibody on consecutive section (d). Examples of a compact Aβ plaque (solid arrow), diffuse Aβ deposit (dashed arrow), and CAA lesion (dotted arrow). CAA, cerebral amyloid angiopathy.

  10. Exposure following weekly dosing with chaducanumab in 9.5- to 15.5-month-old Tg2576 transgenic mice.
    Extended Data Fig. 5: Exposure following weekly dosing with chaducanumab in 9.5- to 15.5-month-old Tg2576 transgenic mice.

    a, b, chaducanumab concentrations in plasma (a), or DEA-soluble brain extract (b) were measured in samples collected 24 h after the last dose in the ‘Chronic efficacy study’. Mean ± s.e. Dotted lines represent the limits of quantitation of each assay. c, Correlations of drug concentrations in plasma (open circles) or brain (open triangles) with administered dose. The average brain concentrations in the two groups receiving the lowest dose were below the limit of quantitation for that assay, which is indicated by a dotted line on the figure.

  11. Treatment with chaducanumab affects plaques of all sizes.
    Extended Data Fig. 6: Treatment with chaducanumab affects plaques of all sizes.

    a, Following weekly dosing of chaducanumab in Tg2576 from 9.5–15.5 months of age, amyloid plaques were stained with 6E10 and quantified using Visiopharm software. b, Plaque size was defined by area, and coloured as follows: <125 μm2 (cyan), 125–250 μm2 (green), 250–500 μm2 (pink), and >500 μm2 (red). c, chaducanumab treatment was associated with a significant decrease in plaque number in all size ranges relative to vehicle-treated controls, with reductions of 58%, 68%, 68%, and 53% in the number of plaques for the <125 μm2, 125–250 μm2, 250–500 μm2, and >500 μm2 groups size, respectively. Mean ± s.e.; statistically significant differences from vehicle for each size range are indicated with asterisks; *P < 0.05, Mann–Whitney test.

  12. Enhanced recruitment of microglia to amyloid plaques following chaducanumab treatment and engagement of Fcγ receptors.
    Extended Data Fig. 7: Enhanced recruitment of microglia to amyloid plaques following chaducanumab treatment and engagement of Fcγ receptors.

    a, b, Brain sections from either PBS- or chaducanumab-treated mice (‘Chronic efficacy study’; 3 mg kg−1 group) were immunostained for Aβ (6E10; red) and a marker of microglia (Iba1; brown). c, The area of individual amyloid plaques was measured, and Iba1-stained microglia were grouped into two categories, either associated with plaques (within 25 μm of a plaque) or not associated with plaques (>25 μm from a plaque). Plaques with circumferences ≥ 70% surrounded by microglia were quantified and stratified based on plaque size. The fraction of plaques that were at least 70% surrounded by microglia was significantly greater in the chaducanumab-treated group (white bars) compared with the PBS control group (grey bars), for plaques ≥250 μm2. Mean ± s.e.; statistically significant differences from vehicle for each size range are indicated with asterisks; *P < 0.05, Bonferroni’s post hoc test following one-way analysis of variance. All quantifications were done using the Visiopharm software. d, e, FITC-labelled Aβ42 fibrils were incubated with different concentrations of the antibodies before adding to BV-2 microglia cell line (d), or primary microglia (e) for phagocytosis experiment measuring uptake of Aβ42 fibrils into the cells by FACS analysis. Mean ± s.d.

Tables

  1. Change from baseline in amyloid PET SUVR values (a secondary endpoint at 6 months), and in exploratory clinical endpoints at the end of the placebo-controlled period (6-month data also shown for amyloid PET)
    Extended Data Table 1: Change from baseline in amyloid PET SUVR values (a secondary endpoint at 6 months), and in exploratory clinical endpoints at the end of the placebo-controlled period (6-month data also shown for amyloid PET)
  2. Incidence of ARIA based on MRI data and ARIA-E patient disposition
    Extended Data Table 2: Incidence of ARIA based on MRI data and ARIA-E patient disposition
  3. Pharmacokinetic data
    Extended Data Table 3: Pharmacokinetic data
  4. Change from baseline in amyloid PET SUVR values, CDR-SB, and MMSE at the end of the placebo-controlled period by absence/presence* of ARIA-E
    Extended Data Table 4: Change from baseline in amyloid PET SUVR values, CDR-SB, and MMSE at the end of the placebo-controlled period by absence/presence* of ARIA-E

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Author information

  1. These authors contributed equally to this work.

    • Jeff Sevigny,
    • Ping Chiao,
    • Thierry Bussière &
    • Paul H. Weinreb
  2. These authors jointly supervised this work.

    • Roger M. Nitsch &
    • Alfred Sandrock

Affiliations

  1. Biogen, Cambridge, Massachusetts 02142, USA

    • Jeff Sevigny,
    • Ping Chiao,
    • Thierry Bussière,
    • Paul H. Weinreb,
    • Leslie Williams,
    • Robert Dunstan,
    • Tianle Chen,
    • Yan Ling,
    • John O’Gorman,
    • Fang Qian,
    • Mahin Arastu,
    • Mingwei Li,
    • Sowmya Chollate,
    • Melanie S. Brennan,
    • Omar Quintero-Monzon,
    • Robert H. Scannevin,
    • H. Moore Arnold,
    • Thomas Engber,
    • Kenneth Rhodes,
    • James Ferrero,
    • Yaming Hang,
    • Alvydas Mikulskis &
    • Alfred Sandrock
  2. Neurimmune, Schlieren-Zurich 8952, Switzerland

    • Marcel Maier,
    • Jan Grimm,
    • Christoph Hock &
    • Roger M. Nitsch
  3. Butler Hospital, Providence, Rhode Island 02906, USA

    • Stephen Salloway
  4. Institute for Regenerative Medicine, University of Zurich, Zurich 8952, Switzerland

    • Christoph Hock &
    • Roger M. Nitsch

Contributions

T.B., P.H.W., M.M., T.E., K.R., J.G. and R.M.N. designed the preclinical studies, and J.S., Y.L., J.G., J.F., C.H., R.M.N. and A.S. designed the clinical study. P.C. led the imaging implementation for the clinical study. T.C. and J.O. were clinical study statisticians. T.B., P.H.W., M.M., R.D., F.Q., M.A., M.L., S.C., M.S.B., O.Q.-M., R.H.S., H.M.A., T.E., J.G. and R.M.N. generated, analysed, and/or interpreted data from preclinical studies. T.B., P.H.W., M.M., R.D., F.Q., M.A., M.L., S.C., M.S.B., O.Q.-M., R.H.S., H.M.A., T.E., K.R., J.G., C.H., R.M.N. and A.S. critically reviewed preclinical sections of the manuscript. J.S., P.C., L.W., S.S., T.C., Y.L., J.O., J.F., Y.H., A.M., J.G., C.H., R.M.N. and A.S. analysed and interpreted clinical study data and critically reviewed clinical sections of the manuscript. All authors approved the final version of the manuscript for submission. Biogen and Neurimmune reviewed and provided feedback on the paper. The authors had full editorial control of the paper, and provided their final approval of all content.

Competing financial interests

J.S., P.C., T.B., P.H.W., L.W., R.D., T.C., Y.L., J.O., F.Q., M.A., M.L., S.C., M.S.B., O.Q.-M., R.H.S., H.M.A., T.E., K.R., J.F., Y.H., A.M. and A.S. are current or former employees and/or shareholders of Biogen. J.S. is an employee of F. Hoffmann-La Roche Ltd., Basel, Switzerland; R.D. is an employee of AbbVie Inc., Worcester, Massachusetts, USA; M.A. is an employee of Substantial Living, San Francisco, California, USA; M.L. is an employee of Novartis, Cambridge, Massachusetts, USA; S.C. is an employee of SynteractHCR, Carlsbad, California, USA; O.Q.-M. is an employee of Shire, Lexington, Massachusetts, USA; R.H.S. and K.R. are employees of Yumanity Therapeutics, Cambridge, Massachusetts, USA; T.E. is an employee of Takeda Pharmaceuticals, Cambridge, Massachusetts, USA; J.F. is retired. M.M., J.G., C.H. and R.M.N. are employees and shareholders of Neurimmune. S.S. was a site investigator for the PRIME study and received consultation fees from Biogen, and has received research support from Functional Neuromodulation, Merck, Genentech, Roche, Lilly, and Avid Radiopharmaceuticals, and consultation fees from Merck, Piramal, Lilly, Genentech, and Roche. He owns no stock options or royalties. Biogen has filed and licensed certain patent applications pertaining to Aducanumab.

Corresponding author

Correspondence to:

Reviewer Information Nature thanks L. Lannfelt, R. Thomas and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author details

Extended data figures and tables

Extended Data Figures

  1. Extended Data Figure 1: Participant accounting. (364 KB)

    PET, positron emission tomography.

  2. Extended Data Figure 2: Amyloid plaque reduction with aducanumab by baseline clinical stage and baseline ApoE ε4 status. (437 KB)

    a, b, Analyses by baseline clinical stage were performed using ANCOVA for change from baseline with factors of: treatment, ApoE ε4 status (carrier and non-carrier) and baseline composite SUVR (a), and for analyses by ApoE ε4 status, using treatment and baseline composite SUVR (b). Adjusted mean ± s.e. ApoE ε4, apolipoprotein E ε4 allele; SUVR, standard uptake value ratio.

  3. Extended Data Figure 3: Amyloid plaque reduction: regional analysis SUVR at week 54. (239 KB)

    The boxed area indicates the six regions included in the composite score. *P < 0.05; **P < 0.01; ***P < 0.001 versus placebo; two-sided tests with no adjustments for multiple comparisons. Adjusted mean ± s.e. Analyses using ANCOVA. SUVR, standard uptake value ratio.

  4. Extended Data Figure 4: Brain penetration of aducanumab after a single intraperitoneal administration in 22-month-old Tg2576 transgenic mice. (825 KB)

    a, b, Aducanumab levels in plasma and brain (a), and plasma Aβ levels after a single dose (b; n = 4–5; mean ± s.e.). c, d, In vivo binding of aducanumab to amyloid deposits detected using a human IgG-specific secondary antibody (c), and ex vivo immunostaining with a pan-Aβ antibody on consecutive section (d). Examples of a compact Aβ plaque (solid arrow), diffuse Aβ deposit (dashed arrow), and CAA lesion (dotted arrow). CAA, cerebral amyloid angiopathy.

  5. Extended Data Figure 5: Exposure following weekly dosing with chaducanumab in 9.5- to 15.5-month-old Tg2576 transgenic mice. (386 KB)

    a, b, chaducanumab concentrations in plasma (a), or DEA-soluble brain extract (b) were measured in samples collected 24 h after the last dose in the ‘Chronic efficacy study’. Mean ± s.e. Dotted lines represent the limits of quantitation of each assay. c, Correlations of drug concentrations in plasma (open circles) or brain (open triangles) with administered dose. The average brain concentrations in the two groups receiving the lowest dose were below the limit of quantitation for that assay, which is indicated by a dotted line on the figure.

  6. Extended Data Figure 6: Treatment with chaducanumab affects plaques of all sizes. (1,561 KB)

    a, Following weekly dosing of chaducanumab in Tg2576 from 9.5–15.5 months of age, amyloid plaques were stained with 6E10 and quantified using Visiopharm software. b, Plaque size was defined by area, and coloured as follows: <125 μm2 (cyan), 125–250 μm2 (green), 250–500 μm2 (pink), and >500 μm2 (red). c, chaducanumab treatment was associated with a significant decrease in plaque number in all size ranges relative to vehicle-treated controls, with reductions of 58%, 68%, 68%, and 53% in the number of plaques for the <125 μm2, 125–250 μm2, 250–500 μm2, and >500 μm2 groups size, respectively. Mean ± s.e.; statistically significant differences from vehicle for each size range are indicated with asterisks; *P < 0.05, Mann–Whitney test.

  7. Extended Data Figure 7: Enhanced recruitment of microglia to amyloid plaques following chaducanumab treatment and engagement of Fcγ receptors. (1,273 KB)

    a, b, Brain sections from either PBS- or chaducanumab-treated mice (‘Chronic efficacy study’; 3 mg kg−1 group) were immunostained for Aβ (6E10; red) and a marker of microglia (Iba1; brown). c, The area of individual amyloid plaques was measured, and Iba1-stained microglia were grouped into two categories, either associated with plaques (within 25 μm of a plaque) or not associated with plaques (>25 μm from a plaque). Plaques with circumferences ≥ 70% surrounded by microglia were quantified and stratified based on plaque size. The fraction of plaques that were at least 70% surrounded by microglia was significantly greater in the chaducanumab-treated group (white bars) compared with the PBS control group (grey bars), for plaques ≥250 μm2. Mean ± s.e.; statistically significant differences from vehicle for each size range are indicated with asterisks; *P < 0.05, Bonferroni’s post hoc test following one-way analysis of variance. All quantifications were done using the Visiopharm software. d, e, FITC-labelled Aβ42 fibrils were incubated with different concentrations of the antibodies before adding to BV-2 microglia cell line (d), or primary microglia (e) for phagocytosis experiment measuring uptake of Aβ42 fibrils into the cells by FACS analysis. Mean ± s.d.

Extended Data Tables

  1. Extended Data Table 1: Change from baseline in amyloid PET SUVR values (a secondary endpoint at 6 months), and in exploratory clinical endpoints at the end of the placebo-controlled period (6-month data also shown for amyloid PET) (122 KB)
  2. Extended Data Table 2: Incidence of ARIA based on MRI data and ARIA-E patient disposition (113 KB)
  3. Extended Data Table 3: Pharmacokinetic data (62 KB)
  4. Extended Data Table 4: Change from baseline in amyloid PET SUVR values, CDR-SB, and MMSE at the end of the placebo-controlled period by absence/presence* of ARIA-E (94 KB)

Supplementary information

PDF files

  1. Supplementary Information (249 KB)

    This includes Supplementary Methods, a Supplementary Discussion and Results, and a list of the PRIME investigators.

Comments

  1. Report this comment #68589

    Chris Exley said:

    I couldn't find the information relating to the vehicle used in the administration of the 'drug' or the composition of the placebo?

  2. Report this comment #68685

    Alfred Sandrock said:

    Aducanumab is supplied in ongoing clinical studies as a liquid drug product for intravenous infusion. A dose of aducanumab is prepared by diluting the required amount of aducanumab liquid drug product (based on dose level and patient weight) into a saline bag. The placebo is a saline bag with no aducanumab added.

  3. Report this comment #68941

    Patrick Fissler said:

    Thank you for that great paper. I couldn't find information about the retest-reliability of the MMSE and the CDR in the study's sample. Would it be possible to provide these information as suggested in a recent review by Simons et al., 2016, in Psychological Science? This would help interpreting the data and is important for power analyses of future studies.

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