pharmacological treatment across dementia syndromes

Pharmacological Treatment Across Dementia Syndromes

Sarah Kremen, MD

Director, Neurobehavior ProgramJona Goldrich Center for Alzheimer’s and Memory Disorders

Department of Neurology, Cedars-Sinai Medical Center

UCLA Intensive Course in Geriatric MedicineSeptember 25, 2021

Disclosures

• I have been a clinical trials Site Principal Investigator for studies sponsored by Biogen, Eli Lilly, Eisai, Genentech, Roche, Merck, and SuvenLife Sciences.

• I have not given any presentations nor promoted any investigational products on behalf of any pharmaceutical company.

• I will discuss off-label use of medications.

Causes of dementia

Encephalitis

Alzheimer’s Disease

HIV

Traumatic Brain Injury

Stroke

Parkinson’s RelatedDementia

Dementia withLewy Bodies

Alzheimer’s Disease (AD)

• AD accounts for 60-70% of dementia cases worldwide

• In the United States, 2021:– More than 6 million Americans of all ages have AD

dementia • 6.2 million ≥65 years old (1 in 9 people)• ~300,000 ≤65 years old

World Health Organization, http://www.who.int/mediacentre/factsheets/fs362/en/.Alzheimer’s Association. 2021 Alzheimer’s Disease Facts and Figures. Alzheimer’s Dementia 2021, 17(3) 327-406.

Risk Factors and Contributors to Alzheimer’s Disease

GeneticsAgingSedentary

Lifestyle

DietEnvironment

Social Interactions

Mental HealthSleep

Smoking

Vascular Health(blood pressure, diabetes,

cholesterol)

Smoking

Education &Brain Resilience

Pathogens/Toxins

Gut MicrobiomeOral Health

Innate ImmunityInflammatory Pathways

Hormonal Regulation (Gender)

Based upon Sweeney et al, 2019

NIA-AA Clinical Diagnostic Criteria (2011):Three clinical stages of AD

• Dementia– Decline in cognition and function– Deficits in ≥ 2 cognitive domains– Positive AD biomarkers

• Mild Cognitive Impairment – Impaired cognition, “intact” function– Other etiologies ruled out– Positive AD biomarkers

• Preclinical – Normal cognition– Positive AD biomarkers– Used for research purposes only

Currently Approved AD Medications

Drug Class/Indication Mechanism of Action

Donepezil(Aricept)

Cholinesterase InhibitorMild to Severe AD

Prevents ACh breakdown

Rivastigmine(Exelon)

Cholinesterase InhibitorMild-Moderate AD (patch: mild-severe AD)

Prevents Ach and butyrylcholine breakdown

Galantamine(Razadyne)

Cholinesterase InhibitorMild-Moderate AD

Prevents Ach breakdownStimulates nicotinic Ach release

Memantine(Namenda)

NMDA antagonistModerate-Severe AD

Blocks toxic effect from excess glutamate, regulates glutamate action

Donepezil/Memantine(Namzaric)

Combination donepezil/memantine XRModerate-Severe AD

Prevents Ach breakdown reduces glutamate toxicity

Formulations and Common Side EffectsDrug Formulation Side Effect

Donepezil(Aricept)

Oral, oral disintegrating, or solution: once daily

GI upset, nausea, vomiting, diarrhea, vivid dreams, weight loss, bradycardia, syncope, increased GI bleeding/peptic ulcer risk


Oral, twice daily;Patch, once daily

GI upset, nausea, vomiting, diarrhea, vivid dreams, weight loss, bradycardia, syncope, muscle weakness, contact dermatitis (patch only)


Oral: immediate release tablet or solution twice daily; XR tablet once daily

GI upset, nausea, vomiting, diarrhea, vivid dreams, weight loss, bradycardia, syncope

Memantine(Namenda)

Oral: capsules (immediate release twice daily; XR once daily); solution

Dizziness, confusion, anxiety, hypotension, hypertension, diarrhea, agitation

Donepezil/Memantine(Namzaric)

Oral: capsules, XR once daily

Combined effects above; rare neuroleptic malignant syndrome, rare rhabdomyolysis

Donepezil (Rogers et al., 1998)

Galantamine (Tariot et al., 2000)

▪ placebo▴ 8 mg/d⧫ 16 mg/d○ 24 mg/d

Rivastigmine (Rosler et al., 1999)

Cholinesterase inhibitors in mild to moderate AD

Donepezil (moderate to severe AD)

Winblad et al., 2006 Farlow et al., 2010

AchEI’s associated with modest reduction in cognitive decline and decreased mortality over 5 years

Xu et al 2021

Memantine (moderate to severe AD)

Reisberg et al., 2004

Combination Therapy in AD

Moderate to Severe ADDonepezil and Memantine

Howard et al., 2012

Memantine + DonepezilTariot et al., 2004

Other Oral Agents (a sample)

• Caprylidene (Axona)• Coconut oil• Curcumin• CoQ10• Huperzine• Vinpocetine• Resveratrol• DHA

Off-Label Use of Approved AD Medications

Drug Disease

Donepezil(Aricept)

Lewy Body DementiaVascular DementiaParkinson’s Disease DementiaTraumatic Brain Injury


Lewy Body Dementia


Severe ADLewy Body DementiaParkinson’s Disease Dementia

Memantine(Namenda)

Lewy Body DementiaMild to Moderate Vascular Dementia

Practical Questions….and Answers

• What medication to use first?– Usually an AchE-I first

• All used in mild dementia• Usually oral

– Can use rivastigmine patch as a second round drug » $$$» sometimes need to show intolerance of oral med to get

approval • Things to consider:

– Heart rate (don’t usually start with HR<55)– Pre-existing GI problems (bleeding, upset, diarrhea)– Low weight


• Will my patient see a big response?– Probably not– Might see improved attention, a little more clarity

• What should I do then?– Titrate up to the max dose if no side effects. If no

benefit, can discuss with patient and family about continuing vs stopping. There’s no clear rule on what to do.


• How do I start my patient on an AchE-I?– Lowest dose for 1 month; if no side effects, increase to

next dosage for 1 month; up to highest dose if not side effects.

• Is it worth it to switch between AchE-I’s if the first doesn’t seem effective?– No clear answer. They’re all about the same.– Sometimes it’s helpful to switch to galantamine

because it has a wider range of dosages.

Practical Questions….and Answers• How do you switch between AchE-I’s?

– If there is good tolerability, then you can just go from one to the next without a break.

– If there are GI side effects, it’s best to give a 7 day break between stopping one and starting another.

• How to ameliorate side effects?– If medication appears to be working but there are GI issues, try

switching from oral med to rivastigmine patch.– Rivastigmine patch eczema -->move patch daily, use Cicaplast or other

similar cream– Nightmares move to am; GI upsetmove to pm– If there is concerning bradycardia, this may not be the appropriate

drug class to use at all.– If there is notable weight loss, maybe this shouldn’t be used

Practical Questions….and Answers• Do you need to taper these medications?

– No rules but probably better to. There are some reports of hallucinations or delirium with abrupt stoppage of donepezil.

– Can taper over 1-2 weeks.

• Is there any time memantine should be considered before or instead of an AchE-I?– If a patient has bradycardia, is severely underweight, has

GI problems– Only in patients who have moderate or severe AD – not

approved for mild AD


• When do I add memantine to an AchE-I?– The two medications are used frequently together.– Add when there is evidence of decline in cognition

or function, despite being on an AchE-I. Usually MMSE is <22.

Practical Questions….and Answers• Are there any interactions between these cognitive

medications and other commonly used medications? – Risk of QT interval prolongation and torsade de pointes:

donepezil and citalopram, escitalopram, venlafaxine– Risk of QT interval prolongation: galantamine and escitalopram– Risk of seizure and increased donepezil exposure: donepezil and

bupropion– Risk of additive bradycardic effects: galantamine and metoprolol

– Memantine doesn’t have much interaction.

– (Drug interactions queried: metoprolol, amlodipine, atorvastatin, simvastatin, metformin, glipizide, repaglinide, citalopram, escitalopram, mirtazapine, venlafaxine)


• Is there any medication approved for mild cognitive impairment (MCI)?– NO– AAN MCI (2017) Guidelines: “There are no high

quality, long term studies identifying pharmacologic or dietary agents that either improve cognition or delay progression in patients with MCI”.

Practical Questions….and Answers• When to stop these medications?

– There is no set guideline– Data does not strongly suggest when to withdraw, or if to withdraw

• Suggested guidance (from Parsons, 2015):– Pt/caregiver decide to stop after receiving advice on pros/cons– Pt refuses– Issues with medication compliance cannot be resolved– Pt cognitive, functional, behavioral decline is worse on treatment– Intolerable side effects– Co-morbidities make treatment risky or futile– No clinically meaningful benefit in continuing therapy– Dementia has progressed to severely impaired stage (Global

Deterioration Stage 7, development of swallowing difficulties)

One more question…There’s a new Alzheimer’s drug out there...now what?

Approved June 7, 2021, Revised Use indications announced July 8, 2021

Aduhelm package insert

Biogen, 2015; Sevigny et al., 2016

PRIME (Aducanumab, Phase Ib) Interim Results: Amyloid Reduction

Biogen, Keynote CTAD 2018

Sperling et al., 2012(bapienzumab study)

ARIA:Amyloid Related Imaging Abnormalities

Aducanumab Phase III Results

Biogen data

Safety: ARIA

ICER Report, May 2021

ARIA-H: 28.3% high dose compared to 8.7% in placebo arms19.1% microhemorrhages, 0.3% macrohemorrhage, 14.7% superficial siderosis

ARIA Overall:Asymptomatic in 74% of cases in high dose arm, 89.7% placebo98% resolved during treatment period, 69% resolved within 12 weeks

Concerns to think about• Methodology

– Post-hoc analysis (see ICER Report for review: https://icer.org/assessment/alzheimers-disease-2021/)

• Side effects– Risk-benefit analysis given the results of the studies

• Cost– Drug– Amyloid PET scans– Genetic testing (ApoE4) required to help guide dosing/safety monitoring– MRI scans (at least 3 within 1 year, possibly more)– Infusion center (space, nursing time)– Neurology check ups– Time (monthly infusions….for how long?)– No coverage currently by any insurance to cover amyloid PET scans or drug --

>waiting to see if this will changeMedicare National Coverage Decision analysis opened July 12, 2021 (proposed decision within 6 months (Jan 2022), final decision 3 months later (Mar 2022)

• Access• Compete with AD clinical trial enrollment• Sets a messy baseline for standard of care meds going forward

On the horizon

• Breakthrough Therapy Designation granted to 2 more amyloid immunomodulators– Lecanemab (Eisai/Biogen, June 23, 2021)– Donanemab (Lilly, June 24, 2021)

Cummings et al, 2020

Dementia with Lewy Bodies (DLB)

• Second most common cause of dementia after AD

• α-synucleinopathy• Can present with similar presentation to

Alzheimer’s disease • Often missed Lewy Body

Taipa R, Pinho J, & Melo-Pires M, Frontiers in Neurology (2012), 3:68 doi: 10.3389/fneur.2012.00068

Dementia with Lewy Bodies (DLB)• Central feature (required): diagnosis of dementia

• Core features (2 or more required for probable diagnosis based on clinical criteria)– Fluctuations in alertness– Visual hallucinations– Parkinsonism– REM sleep behavior disorder

• Dementia symptoms occur at the same time as, or at least 1 year BEFORE, the onset of parkinsonism

McKeith et al., 2017

Symptomatic Treatment• Cognition/Memory

– Treatment same as Alzheimer’s disease– Rivastigmine (Exelon), donepezil (Aricept), galantamine (Razadyne)– Memantine (Namenda)

• Fluctuations and Hallucinations– Rivastigmine (Exelon), donepezil (Aricept), galantamine (Razadyne)– VH second line: atypical antipsychotics (e.g. quetiapine) use with

caution!!!; pimavanserin (off-label)

• Parkinsonism– Carbidopa/levodopa (Sinemet)

• REM Sleep Behavior Disorder– First line: melatonin– Second line: clonazepam

Recent and Current DLB Trials (a sample)

Drug Name/Company

Study Type Therapy Type Target/Symptom

RVT-101; Axovant Phase IIb;Phase II

Small molecule 5HT R6 antagonist;Cognition, function, behavior; Gait

Nelotanserin;Axovant

Phase II Small molecule 5HT 2A inverse agonist;REM sleep BD

E2027; Eisai Phase II Small molecule PDE-9 inhibitor;Cognition

Pimavanserin;Acadia

Phase III Small molecule 5HT 2A antagonist/reverse agonist; 5HT 2C antagonist/reverse agonist;Psychotic symptoms

Mevidalen (LY3154207; Lilly

Phase II Small molecule Positive allosteric D1 R modulator

Alzforum.org, ClinicalTrials.gov accessed May, 2021Outcome not significant

Recent and Current DLB Trials (a sample)Drug Name/Company

Study Type Therapy Type Target/Symptom

Nilotinib;Georgetown Univ.

Phase II Small molecule Tyrosine Kinase inhibitor (TKI), reduces oxidative stress, degrades misfolded. ⍺-synuclein; FDA approved for CML

Bosutinib; Pfizer Phase II Small molecule TKI, targets cAbl, Src KI; FDA approved for CML

K0706; Sun Pharma Advanced Research Company Ltd.

Phase II Small molecule For chronic, accelerated or blast phase CML resistant or intolerant to prior TKI therapy, OR Ph+ ALL

Neflamapimod Phase II Small molecule inhibits p38 mitogen-activated serine/threonine protein kinase (MAPK)

Alzforum.org, ClinicalTrials.gov accessed May, 2021

Vascular Dementia (VaD)

• Accounts for 10-30% of dementia patients• 3rd most common cause of dementia after AD and

DLB• Very common after stroke• Half of all VaD patients may have mixed VaD and

AD pathology• Risk factors: hypertension, hyperlipidemia,

diabetes, cardiac disease, prior strokes, advancing age, ApoE4, smoking

NINDS-AIREN Criteria (1993)• Definite VaD

– Ischemic brain injury on pathology

• Probable VaD– Diagnosis of dementia– History and signs of previous stroke– Neuroimaging evidence of strokes– Stroke and dementia related in time

• Supporting features– Early gait disturbance– Urinary symptoms– Personality changes

Roman et al.,1993

Examples of Vascular Lesions

Treatment for Vascular Dementia• No specifically approved medications• Evidence to support trial of cholinesterase inhibitors

and memantine

• Limited data to support use of CDP-choline, nicergoline, nimodipine, hydergine

• Control risk factors!!!– Treat hypertension, diabetes, hyperlipidemia– Anti-platelet therapy– Exercise, diet modification, smoking cessation

Thank you!

pharmacological treatment across dementia syndromes

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