Journal Club presentation prepared for Stony Brook University, Department of Psychiatry. Explains findings of "The Antibody Aducanumab Reduces Αβ Plaques in Alzheimer’s Disease," Sevigny et al, Nature, Vol 537, 1 September 2016.
Glomerular Filtration rate and its determinants.pptx
Aducanumab Reduces Alzheimer's Plaques
1. The Antibody Aducanumab Reduces Αβ
Plaques in Alzheimer’s Disease
Sevigny et al | Nature | Vol 537 | 1 September 2016
JOURNAL CLUB 14 October 2016
2. 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
4. Current Treatment Options
MILD 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
5. 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
6. 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)
7. 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
10. 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
11. 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
12. Methods
Multi-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
14. Results
Amyloid 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
16. Aducanumab Effect
on CDR-SB and
MMSE over time
Change 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
20. 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)
21. 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!)
Individual monomers (increased either by overproduction or reduced clearance by unknown mechanisms—lipids, hypertension, nutrition, poor metabolism etc) aggregate into damaging oligomers and fibrils that cause an inflammatory response. Through unknown mechanisms, these events lead to aggregation, phosphorylation, and propagation of tau, a protein that is associated with microtubules and is the main constituent of harmful tangles. Affected neurons and synapses become dysfunctional and can die, leading to more inflammatory responses and eventual cognitive decline.
THC
A recent in vitro study published in the Journal of Alzheimer’s Disease,found that low levels of THC (contained in marijuana) reduced the production of soluble Aβ and prevented abnormal accumulation of the protein. This study corroborates the results of previous studies on THC and AD.
Drugs used in other conditions
An increasing body of evidence suggests that insulin resistance contributes to AD. ‘Repurposed’ diabetes drugs have proven to be effective in slowing the rate of structural damage to the brain.
Anticancer drugs that stabilize microtubules (Ex: epotholine D) may help to reduce tau-protein induced damage.
Sildenafil (Viagra) and Tadalafil (Cialis) act as phosphodiesterase type 5 (PDE5) inhibitors, which showed reversal of hippocampal Aβ induced synaptic function damage in a 2013 AD animal-model study.
Gemfibrozil, a drug for the treatment of hyperlipidemia, is currently being studied for its ability to increase miR-107 that down-regulates BACE1, thus preventing the cleavage of APP.
Non-drug approaches
Exercise & diet
This past summer, the results of a randomized controlled Finnish study (FINGER study) revealed evidence that maintaining a healthy diet and exercising prevents structural and functional brain changes associated with cognitive decline. Exercising produces ketone bodies, as a byproduct of breaking down fat and glucose. A 2013 NIA-funded animal study showed that a ketone-rich diet improved learning and memory ability as well as reducing levels of Aβ and tau.
New research from the National Runners and Walkers’ Health Study indicated that running over 15.3 miles per week lowers AD risk by 40% compared with someone who runs less than 4.6 miles per week.
In addition to exercise a recent UCLA study showed that increasing omega 3 fatty acid levels by increasing sleep and vitamin D levels, regulating insulin level through diet, and reducing stress all significantly reversed AD symptoms in patients.
Curcumin (a compound found in turmeric plants)
There has been inconsistent results about its benefit for AD patients, but this past month the FDA granted a patent to Arjuna Natural Extracts Ltd. for their turmeric extract combination, which proved to be beneficial in preventing cognitive decline and reducing Aβ plaques in a series of human clinical trials.
Red wine
Preclinical studies have shown that resveratrol, an antioxidant compound found in red wine and chocolate, may protect the health of neurons by directly activating enzymes known as sirtuins.
Coffee
Drinking 3-5 cups of coffee per day may help protect against AD. According to a report by the Institute for Scientific Information on Coffee, caffeine and polyphenols are the agents in coffee responsible for preventing Aβ and NFT accumulation and reducing inflammation in the brain.
C) Immunological evidence of chimaeric Aducanumab selective for oligomer and fibril and not the monomer
D/E) Immunostaining of Aβ in autopsy brain tissue from a patient with AD with chimaeric aducanumab and 22-month-old transgenic mouse brain tissue with aducanumab
Patients received Aducanumab or placebo once every 4 weeks for 54 weeks
Investigators performed a randomized, double-blind, placebo-controlled, multi-dose phase 1b trial. Dosed patients (n=165) were aged 50-90 years and had positive florbetapir PET scan and clinical signs of prodromal (41%) or mild Alzheimer’s disease (59%). Based on ApoE4 status (65% carriers, 35% non-carriers), patients were randomized to: placebo (n=40) or 1 mg (n=31), 3 mg (n=33), 6 mg (n=30) or 10 mg (n=32) per kg Aducanumab
Patients were stratified to control for ApoE4 status being a confounding variable
The core measures observed in this study included the SUVR changes on PET scan, and changes in MMSE and CDR-SB scores
Placebo began with 40 however the various doses had roughly 30 patients each, and at the end of treatment placebo group ended up with only 30 patients whereas the various doses lost what seems to be a similar proportion until 10 mg, which was found to have the most adverse effects
So to summarize all of these numbers, patients age were between 50 and 90 with a mean of ~72 across the board, equal male and female ratio, stratified by APoE4 carrier status and clinical stage of AD, and their base scores on various clinical measures and PET SUVR composite score. The bottom shows how many patients were concurrently on other AD medication use (which, upon further review, was allowed in the study as long as they had stable use for a minimum of 4 weeks and did not have any dose changes during the study). As you can see, a high percentage of these patients were on concominant medications
In fact, the 10 mg/kg dose was 1.16 after 54 weeks, near the cut point of 1.10 that differentiated between a positive and negative scan
At the top, we see the mean change from baseline in composite SUVR at week 26 and week 54 across treatment groups
At the bottom, we see the actual mean composite SUVR, which as you can see, was roughly equal at baseline across the groups but at week 26 we see a dose dependent decrease in SUVR score, and at 54 we see a more pronounced decrease across groups
MMSE change greatest at 3 mg/kg and 10 mg/kg
NTB- neuropsychological test battery
FCSRT- free and cued selective reminding test
I know all these graphs are beginning to look exactly the same, but it is demonstrating that despite having different baseline clinical stage and apoE4 carrier status, plaque reduction continued regardless in a dose-dependent manner based on this analysis of covariance
The most common adverse effects were amyloid-related imaging abnormalities (ARIA), headache, urinary tract infection, and upper respiratory tract infection. Most appeared to be dose dependent.
During the preclinical studies, dosage was initially intended to go up to 30 mg/kg, however due to the occurrence of microhemorrhage in the mouse models beginning at 10 mg/kg, dosage was not explored further for safety
No patients on placebo developed ARIA-vasogenic oedema (ARIA-E) compared with patients on Aducanumab.
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
All cases of symptomatic ARIA were required to be reported as medically important serious adverse effects. No patients were hospitalised for ARIA.
Owing to the requirement for repeated MRI assessments of those patients who developed ARIA, these individuals were partially unblinded to treatment.
So as seen before, reduction in plaque size was very similar between ApoE4 carriers and non carriers, however it was in the side effect profile that we noted ApoE4 carriers to be correlated with a higher rate of ARIA-E in a dose-dependent fashion
. Post hoc analysis showed that those aducanumab-treated patients who had decreased SUVR scores >1 standard deviation unit relative to placebo-treated patients after one year of treatment experienced a stabilization of clinical decline on both CDR-SB and MMSE scores; whereas, those patients with a smaller or no decrease experienced clinical decline similar to placebo patients (Fig. 2c). The apparent clinical benefit observed in PRIME could also be explained by the binding of aducanumab to oligomeric forms of Aβ, which would not be directly detected by PET imaging. The reductions in SUVR scores may be surrogates for reductions in toxic soluble Aβ oligomers which may have had a more functionally relevant impact on cognition. Whereas significant Aβ reduction was detectable by 6 months, clinical effects were not apparent until one year. Given that clearance of Aβ could be followed by recovery of neuronal function, a lag between reduction of Aβ burden and slowing of disease progression is not altogether surprising. Although the underlying cause of ARIA is not well understood, it is likely that the MRI signal of ARIA is due to increased extracellular fluid. This may be a result of underlying CAA, changes in perivascular clearance and vascular integrity, or local inflammatory processes associated with Aβ-targeting therapies17–20.