Promising drugs in development for Alzheimer [s Disease · Promising drugs in development for Alzheimer [s Disease Rupert McShane Oxford Health NHS Foundation Trust University of

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