Promising drugs in development for Alzheimer s Disease

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1 Promising drugs in development for Alzheimer s Disease Rupert McShane Oxford Health NHS Foundation Trust University of Oxford, Department of Psychiatry

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5 Prime Ministers Challenge Diagnosis of 66% of expected cases

6 Agenda Some biology and terms Stages of drugs development? Overview of all drugs Why are so many failing? Examples Questions

7 Biology

8 Amyloid plaque Tau tangles

9 Inhibits Beta secretase (BACE) Toxicity seems OK Verubecestat

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11 Dominantly Inherited Alzheimer s Network (DIAN) Amyloid Presenilin 1 Paisa mutation Gantenerumab removes it Solanezumab prevents it clumping LY blocks synthesis - β-secretase

12 Lilly has spent $3billion on Alzheimer s research (27y)

13 Nibble: dissolve and neutralise

14 Light up, munch and crunch

15 Sucks it out: peripheral sink

16 Drug development

17 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

18 Boosters ( symptomatic enhancers ): black Delayers ( disease modifying ): green Curer (Both): black then blue

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20 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

21 Current Drugs in Development

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24 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)

25 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)

26 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

27 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

28 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

29 Phases of drug development HCV = Hepatitis C virus MRSA = Methicillin Staph aureus

30 Compare with cancer 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 % failure of disease modifiers in Phase III Cost of Phase III AD trial: $400m

31 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

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33 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 Verubecestat BACE (amyloid) 23 Also for DLB EPOCH MK Prodromal Idalopirdine 5HT6 STARBEAM LuAE S38093 H3 Servier 3 Discontinue d Amlodipine Blood pressure AFFECT 1 Liraglutide Diabetes ELAD 1 Methylene Blue Tau aggregation TauRx 1

34 UK clinical trials gateway 17 dementia trials within 50 miles of Reading 7 within 30 miles CREAD Intepirdine Solanezumab LY TRx 0237 BI TTP488

35 Some interesting ones..

36 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

37 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

38 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.

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40 Glucose vs ketone use Brain fuel one to watch?

41 TPP488 AKA Azeliragon RAGE ligand Multiple effects Stops inflammation Affect amyloid processing 18 month trial N=800 MMSE 21-26

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43 Cranky but you never know.

44 Available Over the Counter Must be used under medical supervision Nutrients to support synapses 1 daily. 3 each DHA & EPA UMP Choline Phospholidids Folic acid B12 Selenium B6 Dietary equivalents 4 tins of tuna, 100g fresh 1kg tomatoes 100g minced beef 4 eggs 1.2kg brocoli Contained in tuna Handful of Brazil nuts 710g spinach Memory: -ve ADL?+ve

45 Available Over the Counter Must be used under medical supervision Nutrients to support synapses 1 daily. 3 each DHA & EPA UMP Choline Phospholidids Folic acid B12 Selenium B6 Dietary equivalents 4 tins of tuna, 100g fresh 1kg tomatoes 100g minced beef 4 eggs 1.2kg brocoli Contained in tuna Handful of Brazil nuts 710g spinach

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48 Where to get more information Scientific detail. US emphasis. Database of current UK trials

49 Thank you Questions

50 UK median annual salary Dementia 2010; Luengo-Fernandez et al for ART

51 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)

52 The effect of Cabernet Sauvignon (Fresno, California) on Alzheimer s mice Pasinetti et al, Mount Sinai, New York but wine consumption related to IQ