Update on Alzheimer’s Research and Clinical Trials

1. Update on Alzheimer’s Research and Clinical Trials Dr Cathy Short Neurologist CALHN Memory Service Department of Neurology The Queen Elizabeth Hospital September 2017 (

2. INTRODUCTION • > 342,800 Australians living with dementia • Will approach 1 million by 2050 unless significant breakthrough in treatment • As of 2015 - 46.8 million people with dementia worldwide • Expected to double every 20 years to approx. • 74.7 million in 2030 • 131.5 million in 2050 • Total estimated worldwide cost of dementia in 2015 → US$818 billion • Cost has increased by 35% since last estimated in 2010 (

3. AD Research • AD research continues both here and internationally in many different areas • We will review some of the following: • treatment - drugs - non- pharmacological therapies • prevention - epidemiology - risk factors • diagnosis - Genetics - biomarkers (imaging, CSF, serum)

4. How long does it take to market a new drug?

5. Clinical Trial phases

6. Current medication for AD • Benefits of Acetylcholinesterase Inhibitors (AChEI’s) first described 24 years ago • Still only symptomatic therapies for AD. • Only 4 drugs available for AD: donepezil, galantamine, rivastigmine and memantine • No new drug has been marketed for nearly 20 years • lack of understanding as to exactly what causes AD – major problem in finding treatment

7. Alzheimer’s Disease Theories • Several theories proposed to explain the cause of AD but so far, no one theory can adequately explain all aspects of the disease • Precise mechanisms for AD progression are also unclear • 3 major theories (Cholinergic, Amyloid, Tau) currently regarded as the most likely explanation for AD • being used as the basis for therapeutic development

8. AD Pathology • brain tissue under microscope • 2 hallmarks of Alzheimer’s disease are: • extracellular amyloid plaques • intra-neuronal neurofibrillary tangles (NFTs) composed of tau • Described in 1907 by Alois Alzheimer they remain the major pathological abnormalities seen in AD

9. Amyloid Cascade Hypothesis • Main focus of research to date • Beta-amyloid (Aβ) is the main component of amyloid plaques (pathological hallmark of AD) • Detailed understanding of how this protein fragment is clipped from it’s parent compound amyloid precursor protein (APP) by two enzymes – beta-secretase and gamma-secretase • Researchers are developing medications aimed at every point in the amyloid processing pathway

10. Aβ cascade hypothesis • Postulated that after amyloid plaques are deposited a cascade follows • Causes inflammation and ultimately formation of neurofibrillary tangles (NFT’s) (hallmark of AD) • Problems with neurotransmitters and neuronal function in the brain and ultimately neurone death

11. New theories about AD Pathology • We now know that tau accumulates in the medial temporal lobes of the brain during normal ageing • Tau doesn’t extend beyond the MTL until Aβ is present in the cortex • Tau PET scanning has allowed us to potentially stage AD in vivo • Amount of tau in the brain correlates very closely with degree of cognitive impairment

12. Anti-Amyloid strategies - Immunotherapy • Initial studies - injecting animals with Aβ → good ab response →cleared amyloid plaques from brains • Human studies prematurely ceased (2002) →development of brain inflammation (meningoencephalitis) in 6% • BUT -evidence that treatment had removed amyloid plaque from the brain • Idea of active immunisation not abandoned – several pharmaceutical companies early phases of developing new active vaccines

13. Anti-amyloid strategies - immunotherapy • Alternative to actively immunising with Aβ, is “passive immunisation” • Bypasses the need to respond to an antigen • Passive immunotherapy leading approach today for disease–modifying treatments • Monoclonal antibodies target various domains of the Aβ peptide to prevent aggregation or speed up removal

14. Monoclonal antibodies • Several monoclonal antibodies have been studied in clinical trials including bapineuzumab and gantenerumab • Stopped prematurely due to lack of perceived efficacy • Subgroups did show benefits leading to further studies • Lack of efficacy thought to be due to underdosing. • Recently restarted studies with Gantenerumab in the same patient group but using larger doses

15. Monoclonal antibodies • Several active ongoing studies • Some early positive results– solanezumab, crenezumab and adecanumab – we await the outcomes of these studies in MCI/mild AD • Phase 3 Solanezumab: failed to meet primary endpoints and slow cognitive decline in AD patients. Trials of this drug are now continuing in prodromal AD patients (the A4 study) – higher doses extending for 3 years. • Phase 3 Adecanumab studies will run until 2022 • Phase 3 Crenezumab studies are still recruiting worldwide

16. Anti-amyloid strategies – reducing production • Another approach to reducing the amount of amyloid in the brain is to reduce the production • Inhibiting enzymes that help produce Aβ means less is produced • BACE inhibitors specifically inhibit the beta-secretase enzyme in the amyloid cascade. • There are a number of studies in progress (at TQEH and RAH) looking at the benefits of BACE inhibition in mild AD

17. Anti-amyloid strategies – reducing production • Other drugs inhibit gamma-secretase – the other main enzyme involved in Aβ production • Problems with unwanted side-effects – skin cancer, rash and hair discolouration • Semagacestat showed promise in early trials but failed to show benefit in phase 3 trials • 2 other gamma-secretase inhibitors have also failed to show benefit • Scientists are still developing more highly selective gamma-secretase inhibitors with less side effects and more effective inhibition of Aβ production.

18. Anti-amyloid strategies – stopping aggregation • Curcumin (a substance in the spice Turmeric) – anti-oxidant, anti-inflammatory and anti-aggregation properties • It binds Aβ and reduces amyloid plaque burden in mice • Preliminary results show reduced rate of cognitive decline in normal healthy elderly receiving curcumin compared to placebo – only short time frame (6 months) and small numbers – larger studies needed. • Limited studies in AD patients have so far failed to show any benefit clinically.

19. Tau • Far fewer drug trials have focussed on tau • No luck so far with anti-Aβ treatments → greater interest in tau • Mouse and primate models of AD show amyloid plaques that respond to anti-amyloid therapy but no tau pathology like human AD • Aged dogs develop AD-like disorder with Aβ and NFT’s • Treatment of these animals with anti-Aβ therapies reduces plaque load but no change in cognition or tau pathology • There is a very robust correlation between tau pathology and clinical measures of dementia

20. Methylthioninium Chloride (Methylene Blue) • First drug targeting tau • Derived from the dye used to stain NFT’s in neuropathological studies • Inhibits tau aggregation • Phase 2 study showed cognitive benefits • Phase 3 trial for mild-moderate AD (both TQEH and RAH) finished February 2016– failed to slow cognitive or functional decline in mild-moderate AD • 30% drop-out due to side-effects • 2nd generation compound (TRx0237) currently in Phase 3 trials for AD and FTD

21. Other tau therapies • Several other drugs that inhibit the development of tau have been studied • Observational studies in geriatric patients taking chronic lithium for BPAD were found to have ↓ risk of developing AD • Lithium inhibits chemical changes in tau that causes formation of NFT’s • Studies on Lithium have been mixed – some have shown benefit with very low doses in MCI, others →worsening confusion – further studies are needed

22. Other tau therapies • Tau immunisations have been studied in animal models and have shown a reduction in the amount of tau and also clinical benefits • Small number of tau immunotherapies currently in phase 1 and 2 testing. • Initial reports are there are no serious adverse effects but still very early

23. Neurotransmitters and Receptors • 5HT6 (serotonin) receptor →promising drug target for Alzheimer’s Disease • Good evidence it’s involved in memory and learning • Antagonism of this receptor→ increase in ACh. • Phase 2 trials showed improved cognition with 5HT rec. antagonist in moderate AD patients already on donepezil • Phase III studies failed to reproduce this result. • Ongoing studies looking at lower doses and giving different AChEI’s

24. Inflammation inAlzheimer's Disease • All chronic neurodegenerative disorders and ageing involve inflammation, oxidative stress and cellular dysfunction →impaired function and loss of brain cells • Brain cells no longer able to participate in neuronal networks needed for cognitive, behavioural and motor function →self-perpetuating cycle of cell injury and ↑ likelihood of more damage • Some research suggests that these inflammatory processes →Aβ and tau accumulation and AD.

25. Anti-inflammatory therapies • Markers of inflammation have been recognised in AD for a long time • Large epidemiological studies have demonstrated a lower prevalence of AD in long term users of NSAID’s • Large number of therapeutic trials of NSAID’s in AD (1993-2004) incl: Ibuprofen, indomethacin, naproxen, celecoxib ,rofecoxib and other anti – inflammatory meds such as prednisolone • All were negative

26. Anti-Inflammatory Therapy • Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT) → primary prevention study of naproxen, celecoxib and placebo in cognitively normal elderly with a first degree relative with dementia • prematurely suspended -↑ cardiac and cerebrovascular events • Both drugs failed to ↓ incidence of AD after 2 years of treatment • 4 year follow-up found those exposed to naproxen were protected from onset of AD by 67% c/w placebo • NSAID’s not considered to be practical treatment option for AD – tolerability and safety issues

27. Anavex2-73 • Media-hype about this trial drug last year • Effects sigma-1 receptors – involved in multiple cellular pathways and physiological processes. • Studies in mice → memory-preserving and neuroprotective effects. • 32 patients, phase 2, 52 week study (Melbourne only) mild-moderate AD → improvements in psychomotor function, attention and working memory. Also improved mood, decreased agitation • Phase 3 double-blind, placebo controlled trial CALHN memory Trials late 2017

28. Vitamins and Anti-oxidants – B12 and Folate • To date there has been insufficient evidence that low levels of vitamin B12 in elderly ↑ risk for dementia or that supplements improve performance • Again, studies looking at folate supplementation have been inconsistent • In 2014 a group of Oxford University researchers assembled all the best clinical trial data involving 22,000 people and concluded that taking B vitamins and folate doesn’t slow mental decline as we age, nor is it likely to prevent AD

29. Vitamins andAnti-oxidants-Vitamin D • Vitamin D – primarily has functions in bone health and metabolism but may also have anti-oxidant and anti-inflammatory properties • not clear whether Vitamin D deficiency is causally related to cognition • Early laboratory evidence that Vitamin D receptor may help regulate clearance of Aβ from the brain • No firm scientific evidence yet that Vitamin D supplementation will have positive effect on cognition

30. Vitamins andAnti-oxidants- E,C,A • Vitamins E, C and beta-carotene (pre-cursor for Vitamin A) – all powerful anti-oxidants • Epidemiological studies show that low intake ↑ dementia risk but association remains inconsistent • Multiple clinical trials provide evidence that supplements with these compounds did not alter cognitive outcomes in MCI, AD or healthy elderly but results still debated • Concern about cardiovascular risk of Vitamin E are likely to prevent further studies of this in AD

31. Vitamins andAnti-oxidants-Ginkgo Biloba • Ginkgo biloba has been studied in trials with mixed results. • Some studies have suggested it improves cognitive performance in MCI • Reasonably firm evidence that it does not alter the risk of dementia or improve cognitive performance in healthy elderly • Potential side-effects of bleeding tendency and drug interactions

32. Vitamins and Anti-oxidants-Fish oil • Omega-3 fatty acids found in fish oil and nuts – thought to be neuroprotective • Studies have failed to show any improvement in cognition in AD patients • In elderly without AD – inconclusive evidence that they may slow cognitive decline • Further large –scale studies needed

33. Mediterraneandiet • Diet is rich in fruits, vegetables, olive oil, legumes, whole grains and fish • Studies have shown that people that closely follow a Mediterranean diet are less likely to have AD than those who don’t • Research suggests that a Mediterranean diet may: • slow cognitive decline in older adults • reduce the risk of MCI progressing to AD • slow the progression of AD and prevent disease-related deaths

34. Diet in AD • A recent study looked at 3 different diets: 1. Mediterranean diet 2. DASH diet (designed to treat hypertension – low salt and sugar) 3. MIND diet (Combination of the above 2 diets)- emphasizes natural plant-based foods, limited saturated fats, encourages consumption of berries and green leafy vegetables (known to specifically benefit brain health)

35. Diet in Alzheimer’s Disease • Those who strictly followed any of these 3 diets had ↓ risk of AD • Even modest adoption of MIND diet approach eg. 2 vegetable servings/week, 2 berry servings/week, 1 x fish meal/week → ↓ risk of AD • Researchers believe making healthy food choices →improved cholesterol and blood sugar levels, better overall vessel health →reduced risk of MCI and AD • Another theory →Mediterranean diet may help prevent brain tissue loss • More studies are needed to know to what degree this diet prevents AD or slows cognitive decline

36. Souvenaid • Medical nutrition supplement specifically for Mild AD→ Omega-3 polyunsaturated FA’s, Uridine, monophosphate, choline, B vitamins and a range of other nutrients • Supports neurones and connections in the early stages of AD • Studies →modest benefits on cognition, memory and daily function in subset of patients in earliest stages of AD • Also delayed shrinkage of hippocampus (important in STM)

37. “Brain Training” • This is quite broad and can include a range of structured mentally stimulating activities such as: • crosswords • learning a new language • reading a book • undertaking further education • Combining mental, social and physical activity in leisure activities are best for reducing dementia risk • dedicated computerised brain training activities →modest effect at improving cognitive performance in healthy older adults • Can intensive computerised training stop progress of cognitive decline and onset of dementia? studies ongoing

38. Physical Activity • Research into potential for physical exercise to reduce the risk of dementia is continuing • Still no randomised trials available yet –several studies have found that physical activity in early, mid and later life is associated with ↓ risk of cognitive decline and dementia • Other studies found people who exercise have slower loss of brain tissue as they age. • People who exercise regularly are less likely to have vascular disease which ↑’s risk of AD

39. Physical Activity • Also beneficial in patients that have dementia • Helps prevent muscle weakness, mobility problems and other health complications associated with inactivity • Also helps reduce symptoms of stress, anxiety and depression • 3 types of exercise should be included in the program– sustained aerobic exercise, weight training and flexibility and balance training

40. Physical Activity • If an exercise program is incorporated in the early stages of dementia it is more likely to be maintained as the condition progresses • Exercise needs to be continued on a regular basis, long term to see benefits on cognition. • Regular aerobic type exercise confers the most benefit for delaying cognitive decline and slowing brain atrophy

41. Insulin Resistance • Insulin resistance and the way the brain processes insulin may be linked to AD • Researchers are exploring the role of insulin in the brain and how brain cells use sugar and produce energy • Researchers have been studying diabetic medications such as pioglitazone which also has potent anti-inflammatory effects

42. Insulin resistance • Preliminary studies with pioglitazone have had mixed results but there is a worldwide 5 year phase 3 study underway (site in Melbourne) • Looking at cognitively normal patients who are considered at risk of developing AD and giving either pioglitazone or placebo and giving placebo to those considered low risk • This study is ongoing and we await the results

43. Vascular disease and Alzheimer’s • Vascular risk factors including • hypertension • heart disease • smoking • high cholesterol • obesity • stroke • diabetes are also risk factors for Alzheimer's disease. • Relationship between vascular disease and AD is complex and not fully understood • vascular disease in the brain thought to lower threshold for clinical expression of AD pathology

44. Vascular disease and Alzheimer’s • Observational studies→ rate of cognitive decline in AD ↓ if vascular risk factors better managed but results inconsistent • Larger, longer randomised controlled trials needed to determine effectiveness of treatment of vascular risk factors in AD • Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER study) →preventative study → combination of diet, exercise, cognitive training and vascular risk factor monitoring in an “at risk” population. • Early 2 year results look promising • Now expanding to UK, Singapore, China and USA

45. Research in Familial Alzheimers Disease • 3 known mutations that cause FAD – accounts for less < 5% of all cases of AD • Several new studies looking at anti-amyloid drugs in asymptomatic patients with either: • one of the known rare genetic mutations OR • strong FHx of AD • will give us more insight into whether treatment at the asymptomatic stage will prevent development of AD

46. AlzheimersPrevention Initiative • Alzheimer’s Prevention Initiative (API) international consortium established to conduct research into an extended family (5000 members) in Colombia South America • Family carry the presenilin 1 (PS1) mutation- effects amyloid processing • API are performing a study on asymptomatic individuals that carry the PS1 mutation using the monoclonal antibody crenezumab vs. placebo • This is a five year study and is still recruiting

47. Dominantly Inherited Alzheimer Network (DIAN) • International initiative funded by the National Institute on Ageing (NIA) in US. • Tracks individuals from families with known AD mutations • Are there physical or mental changes that distinguish those with mutation from those without? • DIAN-TU study- asymptomatic patients with • known mutation or • very high risk of developing AD • Treatment either: solanezumab or ganteneurumabvs. placebo • Still recruiting (one site in Australia at the Austin Hospital) - due for completion end 2019

48. Biomarkers • Diagnosing AD is still essentially clinical • Diagnosis - straight forward if clinically obvious but is challenging when atypical or in very early stages • Diagnostic biomarker would avoid uncertainty and allow definitive diagnosis. • Several clinical trials in progress examining: • brain imaging techniques (eg. Aβ and tau PET) • biomarkers in CSF and blood • Retinal scanning techniques (OCT, angiography)

49. Biomarkers • Access to biomarker →definitive Dx of AD in earliest and most treatable stage • Dx in pre-symptomatic phase would be best outcome → starting treatment before irreversible neurodegeneration has occurred • Pathological changes of AD ( on Aβ PET scans) can be seen up to 20 years before cognitive symptoms appear • Maybe why many trials done in mild-moderate AD have not been effective • Biomarkers may also eventually offer better ways of monitoring response to treatment

50. Outlook • Often no simple solutions to complex problems and AD is a good case in point • Clinical trial results to date have been disappointing for several reasons: • understanding of pathophysiology, range of causes and how AD progresses from pre-clinical to advanced disease still limited. • too much focus on amyloid-directed therapy – need to look at non-amyloid targets such as tau, antioxidants/neuroprotectants and others • giving treatment too late in the disease process