promising drugs in development for alzheimer [s disease · promising drugs in development for...
TRANSCRIPT
Promising drugs in development for Alzheimer’s Disease
Rupert McShane Oxford Health NHS Foundation Trust
University of Oxford, Department of Psychiatry
Prime Ministers Challenge
• Diagnosis of 66% of expected cases
Agenda
• Some biology and terms
• Stages of drugs development?
• Overview of all drugs
• Why are so many failing?
• Examples
• Questions
Biology
Amyloid plaque Tau tangles
Verubecestat Inhibits Beta secretase (BACE) Toxicity seems OK
Dominantly Inherited Alzheimer’s Network (DIAN)
• Amyloid
• Presenilin 1 Paisa mutation • Gantenerumab – removes it
• Solanezumab – prevents it clumping
• LY2886721 – blocks synthesis - β-secretase
Lilly has spent $3billion on Alzheimer’s research (27y)
Nibble: dissolve and neutralise
Light up, munch and crunch
Sucks it out: peripheral sink
Drug development
Big drugs, small drugs
• Small molecules – Eg Donepezil, rivastigmine, galantamine, memantine – Cross the blood brain barrier – Bind to neurotransmitter receptors
• Big molecules – Proteins
• strings of amino acids • Eg antibodies
– Digested in stomach – Need injecting – May not get into brain
Boosters (‘symptomatic enhancers’): black Delayers (‘disease modifying’): green Curer (Both): black then blue
‘Old’ drugs being revisited
• Licensed, so – Skip early phases: much, much cheaper – Marketing more difficult
• Examples – Vitamin E: Positive and replicated – Etanercept: Positive, needs replicating – Nuedexta: Positive, needs replicating – Minocycline: Awaited – Amlodipine: Awaited – Losartan: Awaited – Liraglutide: Awaited
Current Drugs in Development
Overall
• 27% of pipeline is symptomatic
– 33% in Phase 2
• Cholinergic, NMDA
• Other transmitters
• 56% of disease modifying drugs are antiamyloid
• 4 anti-tau agents
– Tau imaging now possible
– May learn from frontal dementia & PSP trials
• Insulin and ‘glitazones’ (PPAR gamma agonists)
93 drugs in development for AD
• ‘Phase III’ drugs – 24 agents in 36 trials
• 7 symptomatic – 3 enhancers, 4 for behaviour – Mean duration 23 weeks – Mean 392 subjects per arm
• 17 disease modifying – 5 amyloid immunotherapy – 8 amyloid small molecules – 4 nonamyloid small molecules – Mean duration – 114 weeks – Mean 516 subjects per arm
– 32/36 pharma; 2/36 NIH + pharma)
45 (of 93) drugs are in Phase II
• 15 symptomatic – 12 enhancers – 3 behaviour – Mean duration 19 weeks – Mean 77 subjects per arm
• 30 disease modifying – 9 amyloid small molecules – 4 amyloid immunotherapies – 10 ‘neuroprotective’ – 6 ‘metabolic’ – 1 anti-tau – 1 stemcell – Mean duration 50 weeks – Mean 67 subjects per arm
• Of 52 trials (of 45 drugs) – 29 are Pharma – 4 NIH – 18 University / Philanthropic
24/93 drugs are in Phase I
• 3 symptomatic
• 21 disease modifying
– 5 amyloid small molecules
– 7 amyloid immunotherapy
– 1 tau immunotherapy
– 1 tau small molecule
– 5 neuroprotective
– 2 metabolic
Conclusions
• Small number in phase I
• ‘Emergence of a repertoire of AD agents that could be tailored to fit individual needs of patients is unlikely’
• Industry, national funders, philanthropists, biotech, universities
– All need incentivising
Phases of drug development
HCV = Hepatitis C virus MRSA = Methicillin Staph aureus
Compare with cancer
• 2014-2015
– 135 trials registered for AD
– 4976 trials registered for cancer
• 19.8% of programmes succeed in cancer
• 99.6% of programmes fail in AD
– No new drugs approved since 2013
– 100% failure of disease modifiers in Phase III
• Cost of Phase III AD trial: $400m
Reasons why trials ‘fail’
• “Wrong patients” – Too late
– Wrong ‘diagnosis’
– Wrong genes
• “Measuring the wrong thing” – Unreliable raters
• “Wrong dose”
• “Wrong additional medication”
• Rarely……. “wrong biological target”
Recruitment: Thames Valley 2013-now Drug Study name Other ID Number
Minocycline Antibiotic MADE 104
Losartan Blood pressure
RADAR 33
Interpidine 5HT6 Mindset Axovant RVT101
23 Also for DLB
Verubecestat BACE (amyloid)
EPOCH MK8931
8 Prodromal
Idalopirdine 5HT6 STARBEAM LuAE58054 6
S38093 H3 Servier 3 Discontinued
Amlodipine Blood pressure
AFFECT 1
Liraglutide Diabetes ELAD 1
Methylene Blue
Tau aggregation
TauRx 1
UK clinical trials gateway
• 17 dementia trials within 50 miles of Reading
• 7 within 30 miles – CREAD
– Intepirdine
– Solanezumab
– LY3314814
– TRx 0237
– BI 425809
– TTP488
Some interesting ones…..
Nuedexta • Licensed for uncontrollable crying / laughing (eg MS or stroke)
– $809 for 60 capsules – Withdrawn from EU for ‘commercial reasons’
• ACTIVE COMPONENT: Dextromethorphan – Eg Robitussin – 100ml = £3.19 Lloyds (20mg=13ml)
• PLUS Quinidine – Blocks metabolism – Grapefruit or pomegranate juice may have same effect – Increases and prolongs concentration
• Caution with slow heart rhythm
• I am not recommending that you try this at home
‘Nuedexta’
• Single trial in • Aggressive or restless AD (~5% in care homes) • N=220 • Schedule
– 20mg DEX (+10mg QUIN) once a day for a week – 20mg DEX (+10mg QUIN) twice a day for 2 weeks – 30mg DEX (+10mg QUIN) twice daily for 2 weeks
• At least moderately improved – Drug 45% – Placebo 27%
• Dizziness, falls may be an issue
Etanercept
• Widely prescribed for rheumatoid arthritis
• Inflammation speeds up decline in AD
– Etanercept blocks inflammation outside brain (TNFα)
– ‘Decoy receptor’ + Fc antibody
• Southampton phase 2 trial
• 6 months N=41
• Subcutaneous injection once a week
• ‘Interesting trends’…….
Brain fuel – one to watch?
Glucose vs ketone use
TPP488 – AKA Azeliragon
• RAGE ligand
• Multiple effects
– Stops inflammation
– Affect amyloid processing
• 18 month trial
• N=800
• MMSE 21-26
Cranky – but you never know….
Available Over the Counter Must be used under medical supervision ‘Nutrients to support synapses’
Dietary equivalents
DHA & EPA 4 tins of tuna, 100g fresh
UMP 1kg tomatoes
Choline 100g minced beef
Phospholidids 4 eggs
Folic acid 1.2kg brocoli
B12 ‘Contained in tuna’
Selenium Handful of Brazil nuts
B6 710g spinach 1 daily. £3 each
Memory: -ve ADL ?+ve
Available Over the Counter Must be used under medical supervision ‘Nutrients to support synapses’
Dietary equivalents
DHA & EPA 4 tins of tuna, 100g fresh
UMP 1kg tomatoes
Choline 100g minced beef
Phospholidids 4 eggs
Folic acid 1.2kg brocoli
B12 ‘Contained in tuna’
Selenium Handful of Brazil nuts
B6 710g spinach 1 daily. £3 each
Where to get more information
• http://www.alzforum.org/therapeutics
– Scientific detail. US emphasis.
• https://www.ukctg.nihr.ac.uk/
– Database of current UK trials
Thank you Questions
UK median
annual salary
Dementia 2010; Luengo-Fernandez et al for ART
What has changed
• Biomarkers – 20-25% of clinical diagnosed AD cases don’t have
amyloid • Financial incentive: paid per recruit • Breadth of definition of ‘AD’: any dementia
– Most trials of anti-amyloid agents now require amyloid imaging • very expensive
– No consensus on best single / combination • CSF (spinal fluid) • MRI • PET (amyloid imaging)
The effect of Cabernet Sauvignon (Fresno, California) on Alzheimer’s mice Pasinetti et al, Mount Sinai, New York
…but wine consumption related to IQ