The Antibody Aducanumab Reduces Αβ Plaques in Alzheimer’s Disease

Sevigny et al | Nature | Vol 537 | 1 September 2016

JOURNAL CLUB 14 October 2016

Alzheimer’s Disease

DIAGNOSIS A definitive diagnosis of AD requires histopathologic examination. The clinical diagnosis of AD requires a decline in both cognition, especially memory, and function, as well as specific neuropathology.

EPIDEMIOLOGY AD is increasingly prevalent with advancing age, and the overall burden of AD is substantial worldwide. The age-standardized prevalence of dementia ranges from 5 to 7 percent in most regions of the world. It has been estimated that the global prevalence of dementia will rise to >100 million by 2050.

RISK FACTORS Aside from age, the most clearly established risk factors for AD are a family history of dementia, rare dominantly-inherited mutations in genes that impact amyloid in the brain, and the apolipoprotein E (APOE) epsilon 4 (e4) allele

Pathophysiology of Alzheimer’s: The Amyloid Hypothesis

Current Treatment OptionsMILD TO MODERATE DEMENTIA MMSE 10-26

› Cholinesterase Inhibitors: Donepezil, Rivastigmine, Galantamine

› Vitamin E: 1000 IU Vitamin E in patients who do not tolerate or want medication

MODERATE TO ADVANCED DEMENTIA MMSE <17

› NMDA Antagonist: Memantine

› 10 mg twice daily in addition to a cholinesterase inhibitor

› Use memantine alone in patients who do not tolerate or benefit from a cholinesterase inhibitor

SEVERE DEMENTIA MMSE <10

› Continue memantine in adjunct with cholinesterase inhibitor

› Consider discontinuation of all medications in palliative cases for quality of life purposes

Current Investigational Modalities“I have not failed. I’ve just found 10,000 ways that won’t work.” – Thomas A. Edison

› Other Monoclonal Antibodies

› ‘Repurposed’ Diabetes Drugs

› Anti-inflammatories

› Anticancer Drugs

› Nicotinic Agonists

› Sildenafil (Viagra) And Tadalafil (Cialis)

› Gemfibrozil

› THC? (Low Levels)

› Diet, Exercise, Coffee, Curcumin, Red Wine, Gingko, Vitamins

Aducanamab

› BIIB037 is a high-affinity, fully human IgG1 monoclonal antibody against a conformational epitope found on Aβ

› Selectively binds to potentially harmful soluble and insoluble Aβ aggregates (oligomers and fibrils) but not monomers

› Also preferentially binds parenchymal over vascular amyloid

› Derived from a de-identified blood lymphocyte library collected from healthy elderly subjects with no signs of cognitive impairment and cognitively impaired elderly subjects with unusually slowed cognitive decline (reverse translational medicine)

Preclinical Studies

› Preclinical studies in plaque-bearing transgenic mice showed reduction of brain Aβ that correlated linearly with dose after chronic dosing

› Aducanumab (chimaeric analogue in the mouse models) found to significantly increase recruitment of microglia to Aβ plaques, suggesting FcγR-mediated phagocytosis of antibody-Aβ complexes as a possible clearance mechanisms

› Histological staining of autopsy tissue of patients with AD or aged amyloid precursor protein (APP) transgenic mice confirm finding of aducanamab to bona fide human Aβ fibrils

Preclinical Studies

PRIME Study (PRIority MEdicine)› In summer 2012, Biogen Idec started PRIME (Priority Medicine), a multicenter, multiple-dose

study of patients with prodromal or mild AD

› Preclinical studies with transgenic mice showed promising results

› 165 patients were randomized and treated between October 2012 and January 2014 at 33 sites across the US

› Patients with prodromal or mild AD and visually positive PET scan were given monthly IV infusions of placebo or Aducanumab at doses of 1, 3, 6, or 10 mg/kg for 1 year

› Study design was a staggered, parallel group design

› This was followed by a 42- month, dose blinded LTE study

› In Phase 1b: Primarily intended to clarify the Aβ-fibril-reducing effects and safety of different Aducanumab doses administered intravenously once a month

Inclusion and Exclusion Criteria

INCLUSION CRITERIA• Age: 50-90• Met Prodromal Dementia Criteria OR

• MMSE 24-30 (inclusive)• Spontaneous Memory Complaint• Objective memory loss (defined as free recall score of

<27 on FCSRT• Global Clinical Dementia Rating of 0.5 • No significant impairment/maintenance of ADLs• Absence of dementia

• Met Mild Dementia Criteria• MMSE 20-26 (inclusive)• Global Clinical Dementia Rating of 0.5 or 1.0• Meeting the National Institute on Aging-Alzheimer’s

Association core clinical criteria for AD

• Passed MRI Screening

• Positive florbetapir PET scan

EXCLUSION CRITERIA

• Negative amyloid PET scan

• Confounding pathology on MRI

• Cognitive impairment caused by other medical condition

• Voluntary withdrawal

MethodsMulti-centered, Randomized, 12-month, Double-blind, Placebo-controlled, Multi-dose Phase 1b Trial

STUDY GROUPS (n=165)› Placebo (n=40) › 1 mg / per kg (n=31)› 3 mg / per kg (n=33) › 6 mg / per kg (n=30) › 10 mg / per kg (n=32)

STRATIFICATION by ApoE4 Status and Clinical Stage of AD

MEASURES› SUVR: Standard Uptake Value

Ratio› MMSE: Mini Mental Status Exam› CDR-SB, Clinical Dementia Rating

—Sum of Boxes

Demographics and Baseline Measures of Study Groups

ResultsAmyloid Plaque Reduction with Aducanumab

›Actually shown to penetrate the brain and decrease Aβ in patients with AD in a time- and dose- dependent manner

›Mean PET SUVR composite score at baseline was 1.44

›After 54 wks of treatment, this decreased significantly (P < 0.001) in the 3, 6, and 10 mg/kg dose groups

›Change in placebo group was minimal

Amyloid PET Images at Baseline and at Week 54

Change in SUVR from Baseline to Week 26 and Week 54

Aducanumab Effect on CDR-SB and MMSE over timeChange from Baseline at Week 26 and at Week 54

› These findings only exploratory at this point

› Analysis of change from baseline of CDR showed dose-dependent slowing of clinical progression after 1 yr tx (P <0.05)

› MMSE also found to have dose-dependent slowing of clinical decline after 1 yr tx (P< 0.05)

› No significant changes from baseline found on NTB or FCSRT

Amyloid Plaque Reduction by Baseline Clinical Stage

Similar Change From Baseline Despite ApoE4 Status

Summary of Most Common Adverse Events

ARIA-E Disposition

Placebo 1mg / kg 3 mg / kg 6 mg / kg 10 mg / kg

Apo E e4 Carrier 0 5% (1) 5% (1) 43% (9) 55% (11)

Non-Carrier 0 0 9% (1) 22% (2) 17% (2)

Total % (n) 0 3% (1) 6% (2) 37% (11) 41% (13)

Discussion

STRENGTHS

• Aducanumab found to penetrate brain and decrease Aβ in a time- and dose- dependent manner

• Analysis of CDR-SB and MMSE changes after 1 year provide support of clinical benefit

• Post hoc analysis showed that treated pts who had decreased SUVR scores >1 standard deviation unit relative to placebo experienced a stabilization of clinical decline on both CDR-SB and MMSE scores

• The main safety finding, ARIA-E, was dose-dependent and more common in ApoE ε4 carriers, (consistent with findings with other anti-Aβ monoclonal antibodies 7,16,17.)

WEAKNESSES• Only in phase 1b study (only meant to demonstrate safety

and tolerability at this time and not efficacy)

• Staggered parallel-group design

• Small sample sizes

• Limited region (USA only)

• Possible partial unblinding due to ARIA-E

• A high percentage of patients were on concurrent AD medications

• Phase 3 trials are ongoing (currently recruiting study subjects) and it could be until 2020-2022 until study is completed (however, if successful…..could be a game changer!)

Questions?