Dementia TREATMENT Research Update 2019 · Dementia TREATMENT Research Update 2019 Dr. Jared R....
Transcript of Dementia TREATMENT Research Update 2019 · Dementia TREATMENT Research Update 2019 Dr. Jared R....
Dementia TREATMENT Research Update 2019
Dr. Jared R. Brosch, M.D., M.Sc.Associate Professor of Neurology
Associate Program Director Neurology ResidencyIndiana Alzheimer’s Disease Center
Do Not Replicate without Permission
• Disclosures– Dr. Brosch receives support from the following companies for
dementia clinical trial work:• Abbvie• Accera• Axovant• Avanir• Biogen • C2N/Abbvie• Eisai• Eli Lilly• Genentech• Roche• Lundbeck• Chase Pharmaceuticals• TauRx
– I use images in this presentation that are freely available and give credit with URLs to the image
• Objectives
– Lifestyle Hot Topics– Alzheimer’s drug development– Other Neurodegenerative diseases
https://hhp-blog.s3.amazonaws.com/2017/06/iStock-516447314.jpg
• Three Major Studies Show Lifestyle Matters!!
https://images.agoramedia.com/everydayhealth/gcms/Why-the-Mediterranean-Diet-Could-Save-Your-Life-722x406.jpghttp://c1.thejournal.ie/media/2014/06/shutterstock-147680771-390x285.jpghttps://scx1.b-cdn.net/csz/news/800/2017/cognitivecro.jpghttps://www.medicalnewstoday.com/content/images/articles/323/323252/glass-of-wine.jpghttps://upload.wikimedia.org/wikipedia/commons/thumb/6/6b/No_Smoking.svg/2000px-No_Smoking.svg.png
• Three Major Studies Show Lifestyle Matters!!
https://images.agoramedia.com/everydayhealth/gcms/Why-the-Mediterranean-Diet-Could-Save-Your-Life-722x406.jpghttp://c1.thejournal.ie/media/2014/06/shutterstock-147680771-390x285.jpghttps://scx1.b-cdn.net/csz/news/800/2017/cognitivecro.jpghttps://www.medicalnewstoday.com/content/images/articles/323/323252/glass-of-wine.jpghttps://upload.wikimedia.org/wikipedia/commons/thumb/6/6b/No_Smoking.svg/2000px-No_Smoking.svg.png
• 2.5 hours a week of moderate intensity exercise.
• 20-30 minute blocks of time• Brisk walk• Elliptical• Recumbent bike• Zoomba• Pickleball• Any activity that gets heart rate elevated
for 20-30 minutes• Some reports that FAR LESS than 50% of
all those over 60 years of age achieve this goal.
• Three Major Studies Show Lifestyle Matters!!
https://images.agoramedia.com/everydayhealth/gcms/Why-the-Mediterranean-Diet-Could-Save-Your-Life-722x406.jpghttp://c1.thejournal.ie/media/2014/06/shutterstock-147680771-390x285.jpghttps://scx1.b-cdn.net/csz/news/800/2017/cognitivecro.jpghttps://www.medicalnewstoday.com/content/images/articles/323/323252/glass-of-wine.jpghttps://upload.wikimedia.org/wikipedia/commons/thumb/6/6b/No_Smoking.svg/2000px-No_Smoking.svg.png
• Mediterranean Style Diet• VEGETABLE based diet• DE-EMPHASIZE: red meat, butter,
cheese, pastries, sweets, simple carbs• Healthier protein choices – vegetable
protein, fish/chicken• Mixed nuts• Legumes• Healthy oils – olive oil
• Three Major Studies Show Lifestyle Matters!!
https://images.agoramedia.com/everydayhealth/gcms/Why-the-Mediterranean-Diet-Could-Save-Your-Life-722x406.jpghttp://c1.thejournal.ie/media/2014/06/shutterstock-147680771-390x285.jpghttps://scx1.b-cdn.net/csz/news/800/2017/cognitivecro.jpghttps://www.medicalnewstoday.com/content/images/articles/323/323252/glass-of-wine.jpghttps://upload.wikimedia.org/wikipedia/commons/thumb/6/6b/No_Smoking.svg/2000px-No_Smoking.svg.png
• Cognitive Exercise• 20-30 minutes a day• NOT TV WATCHING• Many studies used computer based
games• No clear evidence on what is best• Social activity may count!• Crosswords, Sudoku, Word finds,
workbooks• Art projects
• Three Major Studies Show Lifestyle Matters!!
https://images.agoramedia.com/everydayhealth/gcms/Why-the-Mediterranean-Diet-Could-Save-Your-Life-722x406.jpghttp://c1.thejournal.ie/media/2014/06/shutterstock-147680771-390x285.jpghttps://scx1.b-cdn.net/csz/news/800/2017/cognitivecro.jpghttps://www.medicalnewstoday.com/content/images/articles/323/323252/glass-of-wine.jpghttps://upload.wikimedia.org/wikipedia/commons/thumb/6/6b/No_Smoking.svg/2000px-No_Smoking.svg.png
• No smoking• Enough said• Probably affects cognition through
vascular disease• Potent known vascular risk factor
• Three Major Studies Show Lifestyle Matters!!
https://www.medicalnewstoday.com/content/images/articles/323/323252/glass-of-wine.jpghttps://cdn.prod-carehubs.net/n1/802899ec472ea3d8/uploads/2018/02/an-illustration-of-equivalent-amounts-of-beer-hard-alcohol
• Zero or Moderate Alcohol consumption• Don’t start drinking now• If you do, limit to ONE DRINK per night• If you skip a few nights, try not to “catch
up” for the week• No safe known amount of alcohol for
the body/brain• Seems to have some cardiovascular
benefit in low amounts, perhaps may help with cerebrovascular blood flow
• AREA OF UNCERTAINTY
• Three Major Studies Show Lifestyle Matters!!– FINGER STUDY
• Finnish Geriatric Intervention Study, 1300 people• 25% improvement in test scores, could delay onset and
reduce burden of AD– UK STUDY
• 200,000 adults >60yrs of age• 32% reduction in risk of dementia over 8 years
– RUSH STUDY• 2000 people• 60% reduction in rate of developing AD over 6-9 years in
people who adopted all lifestyle changes REGARDLESS OF GENETIC RISK PROFILE!!!
https://jamanetwork.com/journals/jama/article-abstract/2738355?guestAccessKey=c635f7cd-e7f5-4956-85f1-71950acad390&utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_content=tfl&utm_term=071419https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60461-5/fulltexthttps://www.aarp.org/health/dementia/info-2019/healthy-lifestyle-alzheimers.html
• Drug Development Update– Approved Drugs WORK
• Donepezil (Aricept)• Rivastigmine (Exelon)• Galantamine (Razadyne)• Memantine (Namenda)
– NOT MEMORY ENHANCERS– Slow progression of Alzheimer’s and prevent need
for nursing home placement by YEARS
• NEW Drug Development Update
https://www.orthocuban.com/2016/08/continuing-debate-over-scientific-research/
• Drug Development Update• 2015 Data
https://browzine.com/articles/54105797
• Drug Development Update
http://www.neurology.org/content/69/9/E8/F1.large.jpg
http://www.nature.com/gim/journal/v10/n4/images/gim200836f2.jpg
Intracellular TAUExtracellular AMYLOID
• Drug Development Update– Amyloid Hypothesis graph
https://www.nature.com/articles/d41586-018-05718-5
• Drug Development Update– Amyloid Passive Vaccination
• Caused meningoencephalitis!– Anti-Amyloid monoclonal antibodies
• Bapineuzumab (brain hemorrhages)• Solanezumab (still in 2 active studies)• Gantanerumab (in 1 active study)• Crenuzumab (in 1 active study)• Aducanumab (terminated?)• BAN2401 (in 2 active studies, and potentially 2 more)• Donanemab (in 1 active study)
https://www.nme.com/blogs/nme-blogs/terminator-6-dark-fate-release-date-cast-trailer-2451500
• Drug Development Update– Picture of Amyloid molecules showing soluble,
insoluble, monomers, polymers
https://www.bioarctic.se/en/alzheimers-disease-2541/
SolanezumabCrenezumab
GantenerumabDonanemabBapineuzumab
AducanumabBAN2401
• Drug Development Update
https://www.bioarctic.se/en/alzheimers-disease-2541/
• Drug Development Update– Aducanumab Announcement Oct 22, 2019
• Futility analysis led to cessation of all trials in 2019• As all data was collected the following was found:
– EMERGE – MET PRE-SPECIFIED PRIMARY END-POINT!!!» HIGH dose group only. CDR 23% better (reduction in
clinical decline) in treatment than placebo, MMSE 15%, ADAS-Cog 27%, ADCS-ADL 40%.
» Amyloid plaque burden reduced, Tau levels in spinal fluid also changed
– ENGAGE – early terminated, but patients who received sufficient exposure to high dose had similar findings
https://www.medpagetoday.com/neurology/alzheimersdisease/82865
• ADUCANUMAB
https://www.nature.com/articles/nature19323
• Drug Development Update– Aducanumab Announcement
• Side Effects– ARIA-E
» Amyloid Related Imaging Abnormalities – Edema• Leads to headaches• Swelling of small areas of brain on MRI scan• Few to no symptoms clinically other than headache• Resolves spontaneously in 4-16 weeks• Most without any long-term issues
https://www.quora.com/What-is-ARIA-E-And-how-does-amyloid-beta-and-tau-immunotherapy-all-relate-to-it
• Drug Development Update– Aducanumab Announcement Oct 22, 2019
• So many things to think about!– First – AWESOME– Second – Who pays? Will this BREAK MEDICARE?– How will people be deemed eligible? Will we need expensive
PET scans to be approved to?– Complicates further clinical trials because now this becomes
the standard of care? – Negative Amyloid PET scans?– Lastly - AWESOME
https://www.bioarctic.se/en/alzheimers-disease-2541/
• Drug Development Update– Secretase inhibitors
https://www.mybraintest.org/2013/lilly-kills-a-bace-inhibitor-trial-for-alzheimers/
• Drug Development Update– Secretase inhibitors
• Gamma– Furthest along was semagecestat (Lilly) – Phase 3– No improvements in cognition, increased infections and rate of
skin cancer– TERMINATED
• Beta (BACE)– Proven in SEVERAL studies to MAKE COGNITION WORSE, no other
significant side effects– Theoretical issues with retinal depigmentation and skin
depigmentation but not seen in humans– Outstanding question is that these may be viable drugs with
lower amount of secretase inhibition, but cold feet
• Drug Development Update– Tau Drugs
• Drug Development Update– Tau Drugs
• Drug Development Update– Tau Drugs
• Anti-Tau monoclonal antibodies– Most in Phase 2– Stopped early in one study in Progressive Supranuclear palsy
(a Tau based disease)– Data slowly emerging in the next year
• Tau passive immunization• Anti-sense Oligonucleatides (ASO) against Tau
• Drug Development Update– Other Drugs
• Phosphodiesterase Inhibitors• Coconut Oil Derivatives• Riluzole derivative• Diabetes drugs (RAGE)• Drugs affecting the Gut Microbiome• Drugs affecting Inflammation• Drugs targeting Immune cells in the Brain• Seizure drugs• Deep Brain Stimulation• Transcranial Magnetic Stimulation• ETC!
• Drug Development Update– Other Drugs
• Phosphodiesterase Inhibitors• Coconut Oil Derivatives• Riluzole derivative• Diabetes drugs (RAGE)• Drugs affecting the Gut Microbiome• Drugs affecting Inflammation• Drugs targeting Immune cells in the Brain• Seizure drugs• Deep Brain Stimulation• Transcranial Magnetic Stimulation• ETC!
https://ars.els-cdn.com/content/image/1-s2.0-S2352873717300379-gr1_lrg.jpg
• BEYOND Alzheimer’s disease– Many other neurodegenerative diseases exist and
need support!
http://tbrnewsmedia.com/medical-compass-parkinsons-disease-reducing-risk-and-slowing-progression/https://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&ved=2ahUKEwii1eOHhbHlAhUET6wKHUVnCEoQjRx6BAgBEAQ&url=https%how-stroke-overview&psig=AOvVaw3qE4v1qjpevEUucHcXtdpg&ust=1571873984490151
Dementia
Alzheimer’sDementia
Parkinson’s Disease Dementia
LewyBody Dementia
Fronto-Temporal Lobar Dementia
Progressive SupranuclearPalsy/CorticobasilarDegeneration
Vascular Dementia
Multiple Systems Atrophy
Many Others!
Dementia Neuropathology
Tauopathies
• PSP• CBD• FTLD with Parkinsonism
(Chr17 – MAPT)• Pick’s Disease
Alpha-Synucleinopathies
• Parkinson’s Disease• Lewy-body
Dementia• Multiple Systems
Atrophy
Amyloid-beta/Tau
• Alzheimer’s disease
• FTLD several forms including:• FTD-ALS C9ORF72 (12/25%) familial (TDP-)• FTD Progranulin (Also Chr17) (TDP+)• FTD-FUS (Fused in Sarcoma) (TDP-)
Other
• BEYOND Alzheimer’s disease– Vascular dementia is #2!
• Can be caused by multiple strokes, or from an accumulation of small blood vessel damage.
• Similar to what is seen in End Stage Multiple sclerosis• Significant gait impairment, bladder dysfunction, severe
slowing of thought process/motor systems.• “Step-Wise” decline – often have abrupt changes in
functionality that don’t improve.• Treat risk factors, keep active• Local Stroke Support Groups (Community, RHI, Franciscan,
etc)
• BEYOND Alzheimer’s disease– Lewy Body Dementia’s
• Parkinson’s disease dementia + Dementia with Lewy bodies
• Hallucinations (starts with visual), Dream Enactment, BIG fluctuations in attention/alertness
• TRADE-OFF’s – treat the Parkinson’s part (worse thinking), treat the hallucinations (worse Parkinsons).
• Profound response to Cholinesterase Inhibitors• Shorter life-span (dementia + mobility/falls!)
• BEYOND Alzheimer’s disease– Lewy Body Dementia’s
• Clinical Trials– 5HT6 drugs (terminated)– 5HT2A drugs (terminated)– Phosphodiesterase Inhibitors (recruiting)– D1PAM drug (recruiting)
• Rock Steady Boxing, The Climb• Local DLB Support Group (Zionsville)
https://consultqd.clevelandclinic.org/research-collaborative-launched-to-advance-progress-against-lewy-body-dementia/
• BEYOND Alzheimer’s disease– Frontotemporal Dementia
• Language Presentation• Behavioral Presentation
– Young, loss of social etiquette, can be difficult to manage in memory care
– Supportive treatments only, other drugs may worsen
• FTD Support Group (Joy’s House)• NEW clinical Trials – Phase 1 – MUST KNOW GENETIC
STATUS!
• Questions?