Prescribing Memory Medications: Purpose and Value

By: Ryan Townley, MD

Cognitive and Behavioral Neurology Fellowship Director

Co-Director of Research Education Core

Assistant Professor

KU Alzheimer’s Disease Center

Objectives

• FDA approved drug timeline

• When to start medications?

• Tips for dealing with side effects• Creative dosing, alternative options

• When to stop medications?

• What about Aducanumab (Aduhelm)?• Best practices guidelines

Disclosures

• I will discuss “off-label” use of acetylcholinesterase inhibitors• Mild cognitive impairment (MCI)

• Lewy body disease: MCI and dementia

• I have written an article titled:

https://ordinary-times.com/2021/06/10/alzheimers-disease-aduhelm-and-the-fear-of-false-hope/

FDA Approved Treatments for AD

1996 –Donepezil

2000 –Rivastigmine

2001 –Galantamine

2003 –Memantine

2014 –Namzaric –

memantine + donepezil

2021 –Aducanumab

(Aduhelm)

• Acetylcholinesterase inhibitors:• Donepezil• Galantamine also nicotinic modulator• Rivastigmine also

• NMDA receptor antagonist:• Memantine

• These drugs are okay for AD…

• AChE drugs work much better in Lewy Body disease…

• Aducanumab … ???

Cholinergic Hypothesis

• Acetylcholine• Cognitive neurotransmitter

• Attention, focus, working memory, memory

• Broken down between synapses by acetylcholinesterase • Goal of these drugs = block this

MCI can be hard to diagnose

• Alzheimer's Disease Cooperative Study used for guidelines suggesting no evidence for use in MCI

• 30% of patients misclassified as MCI • Identified as cognitively normal based

multiple cognitive tests

• Probably subjective cognitive impairment

Edmonds, Emily C., et al. "Unmasking the benefits of donepezil via psychometrically precise identification of mild cognitive impairment: A secondary analysis of the ADCS vitamin E and donepezil in MCI study." Alzheimer's & Dementia: Translational Research & Clinical Interventions 4.1 (2018): 11-18.

Subjective cognitive decline

Jessen, Frank, et al. "A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease." Alzheimer's & Dementia 10.6 (2014): 844-852.

MCI to Dementia Conversion Rate

• Removal of “false-positives” unmasked beneficial effects of donepezil on cognition and rate of progression to Alzheimer's disease

Edmonds, Emily C., et al. "Unmasking the benefits of donepezil via psychometrically precise identification of mild cognitive impairment: A secondary analysis of the ADCS vitamin E and donepezil in MCI study." Alzheimer's & Dementia: Translational Research & Clinical Interventions 4.1 (2018): 11-18.

Alzheimer’s Dementia Short Term Data

• 2003 Feldman Study: • Slowed loss of iADLs/ADLs

• Delay long term care placement

• Lower levels of caregiver stress

• Most studies are 24 weeks with rare ones being 52 and 104 weeks

Feldman, Howard, et al. "Efficacy of donepezil on maintenance of activities of daily living in patients with moderate to severe Alzheimer's disease and the effect on caregiver burden." Journal of the American Geriatrics Society 51.6 (2003): 737-744.

Long Term Data

• 2021 Swedish Dementia Registry • 5-year data in > 16,000 patients

• Reduced mortality• All AChe significant

• Consistent with prior studies (reduced stroke, MI)

• Galantamine > donepezil/rivastigmine

• Reduced conversion to severe dementia• All had lower hazard ratios

• Galantamine reached statistical significance

Should My Patient Be on an AChEI?

• For Lewy body disease – ABSOLUTELY YES• MCI or dementia

• For Alzheimer’s dementia – YES• Young-onset working memory/dysexecutive variants• Short term data suggests modest stability in testing scores• Long term data suggests mild reduced mortality

• For MCI due to probable Alzheimer’s disease - PROBABLY – “Off-label”

• For vascular disease – PROBABLY NOT• Large overlap with Alzheimer’s cases can see some mild benefit

• For frontotemporal disease – NO• Can worsen behavioral symptoms (they are not Ach deficient)

Cholinesterase Inhibitor Tips

• Start with donepezil – give in the morning with protein meal• Increase from 5 mg to 10 mg in 4 weeks

• If GI symptoms: try splitting doses, 5 mg in morning/5 mg at dinner

• Some try going to 15 or 20 mg (split doses)• Benefits in DLB and working memory AD

• 23 mg SR tablet (same bioavailability as 20 mg BID)

• Nighttime = insomnia, nightmares, REM Sleep Behavior Disorder

• Galantamine oral • 8 mg -> 16 mg -> 24 mg

• ER version or twice daily version

Cholinesterase Inhibitor Tips

• I don’t use rivastigmine oral

• If GI side effects – try a rivastigmine patch• Dosing: 4.6 mg -> 9.5 mg (standard) -> 13.3 mg

• Allergic contact dermatitis VERY RARE (most are irritant contact dermatitis)

• Rotate skin site each day (not using same one in 10-14-day period)

• Careful removal of patch (during shower)

• Good skin care: use moisturizes, hydration

• Topical corticosteroids as needed

Sadowsky, Carl H., et al. "Rivastigmine from capsules to patch: therapeutic advances in the management of Alzheimer’s disease and Parkinson’s disease dementia." The primary care companion for CNS disorders 16.5 (2014).

GoodRX.com

Cholinesterase problems

• Diarrhea, nausea, vomiting• Acetylcholine helps you digest food

• Drug is increasing availability

• Rivastigmine oral 40-45%

• Donepezil ~20-25%,

• Rivastigmine patch ~5-6%

• Muscle Cramps

• What about the heart?• Lightheadedness and fatigue may

be first clues

• Bradycardia, prolonged qTC• Baseline EKG followed by after steady

state EKG

• Cardiology consult if needed

• Galantamine may be slightly less qTC issue than donepezil

When should I stop an AChEI?

• When the negatives outweigh the positives• Significant weight loss

• Anorexia

• Excessive diarrhea

• Excessive muscle cramping

• Lightheadedness, fatigue, lethargy

• Consider trialing different AChEI though• Patch form or ER form for GI symptoms

Should I Start Memantine?

• Alzheimer’s disease – moderate to severe dementia• FDA approved

• May help with behavioral symptoms

• Usually well tolerated

• Some evidence of synergistic effect with donepezil• Mild cognitive benefit – unclear clinical significance

• Lewy body disease – evidence is less clear

• Frontotemporal disease – no benefit

• Combo drug Namzaric – costs more, lowers pill burden

What About Aducanumab?

• Anti-amyloid antibody • Triggers immune system to clear amyloid

plaque pathology

• FDA approved for clearing amyloid, clinical benefit indeterminant• Original Biogen study was terminated early

due to futility analysis

• Additional analysis yielded mildly positive results in 1 study and pooled data

Aducanumab Clinical Development

• Phase 3/3b: (2015-present)• Targeting A+ individuals with mild cognitive impairment and mild dementia

• Over 3,200 participants across 348 sites in 20 countries• Study 301 (ENGAGE), n = 1653

• Study 302 (EMERGE), n = 1643

• Both studies needed to be positive

Study 302: Primary Endpoints

ADI- Alzheimer’s Disease International 2021 Webinar: Aducanumab Data Review Samantha Budd Haeberlein, PhD Senior Vice President, Head Neurodegeneration Development Unit Biogen – January 14th, 2021

Where is the truth?

• Both 301/302 trials were initially stopped with a futility analysis• If both studies were not positive – prespecified outcome was not met

• Further data: Study 301 was negative; Study 302 was positive

• Why the difference?• Biogen: “Lower exposure to 10 mg/kg dosing in Study 301”

• Sub analysis of Study 301 patients who had full 10 mg/kg dosing = Study 302 effects

• Biogen: “Imbalance in number and distribution of rapid progressing AD patients in study 301”• Placebo groups progressed at different rates, 301 slower than 302• Alternatively – Study 302 had an imbalance of faster progressors in placebo group and

thus the drug was not the cause of the slowed decline• Heterogeneity of progression in MCI and early AD is high

• “If you test a hypothesis 20 times and you get 1 positive result…”

What are the risks/benefits doc?

• Known risks• 35% develop brain swelling

• 6% develop small brain bleeding

• Major cost - $56,000 per year sticker price• Multiple MRI scans throughout the year

• Additional infusion costs – more like $100,000/yr

• Insurance coverage and Biogen financial assistance details still unknown

• And for what benefit?• It is unclear

Practice Guidelines for Aducanumab

• Age 50-85, not on anticoagulation, must be able to get MRIs

• Mild Alzheimer’s disease: MCI to mild dementia• MMSE 21-30 or MoCA 17-30

• Biomarker proven disease• Cerebrospinal fluid biomarkers or Amyloid PET

• NOTE: I don’t like only Amyloid PET being used

• Baseline MRI within 1 year• Susceptibility weighted imaging with < 5 microbleeds• No marked vascular disease

• Discuss getting APOE4 genotyping• APOE4 with increased risk of ARIA – may require more frequent MRIs

Administering Aducanumab In Practice

• Monthly infusions at an infusion center

• At least 4 MRIs within a year (more if ARIA occurs)

Questions