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

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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