© Copyright 2016 Quintiles

“2016 – is this the end of the 100 year plus battle against AD”?

Dr Lynne Hughes and Susie Boyce, 16 June 2016

Note: This is our personal view not an official company view.

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• Clinical trials are the scientific process for measuring whether new drugs are safe and effective.

• James Lind, physician (1747) pioneered the field of clinical research > Discovery Citrus fruits prevented scurvy.

• Sir Austin Bradford Hill, epidemiologist (1946) 1st randomised controlled trial (RCT) Streptomycin to treat tuberculosis

• Regulatory agencies have used clinical trials ever since to determine whether a new drug is ready for the public.

• 1019 Novel drugs approved by the FDA

Introduction to Clinical Trials

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Drug discovery

Pre clinical testing Phase I Phase II Phase III Licensing

Approval

4.5 years 5.5 years 7 years 8.5 years 11 years 12.5 years

£436 million

£533 million

£710 million

£916 million £1.1 billion £1.15

billion

5,000 – 10,000

candidates10-20

candidates5-10

candidates2-5

candidates1-2

candidates 1 medicine

Drug Development Process

Reference source: abpi publication Time to flourish Inside innovation; the medicine development process

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The Rocky Road of Research in Alzheimer’s DiseaseSo, what is Alzheimer’s Disease?

1906 AD was 1st described by German neuropathologist: Alois Alzheimer

A devastating progressive neurological disease characterized by progressive loss of memory and cognitive functions, decline in functional capacity and alteration in behavior.

We still do not know the cause

The only disease in the top 10 leading causes of death that cannot be prevented, cured or even slowed down.

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First Documented Case of Premature Disease of Forgetfulness50-year old woman from Germany in 1901

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Why is this a problem?

Key facts: 2013 World Alzheimer’s ReportGlobal Prevalence of dementia

46, 8 million in 2015 For 2015, we estimate over 9.9 million new cases of dementia each year worldwide, implying one new case every 3.2 seconds. This new estimate is almost 30% higher than the annual number of new cases we estimated for 2010 131.5 million in 20506-8% of all persons older than 65 have AD

30% of population over 85 have ADLess than 10 million AD patients are treatedRequiring Care:

Half of all dementia sufferers80% of nursing home patients

This is an increasing Global Challenge with an aging population

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Most costly in U.S. direct health expenditures

Most costly in informal care costs

Fastest accelerating disability burden

The cost of AD globally is $800B1

Imperative for a Solution:Humanitarian and Economic Burden

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Cancer

Heart Disease

AD

65 70 75 80 85 90 95 100 105 110

77

102

109

Direct Health Expenditures (billions)

Alzheimer’s Disease International. World Alzheimer Report 2015. http://www.alz.co.uk/research/world-report-2015. Accessed February 2016

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Increasing longevity is driving the incidence of Alzheimer's

There are 3 super-aged countries today and there will be 30 within the next 15 years

Only major killer without a means of slowing, preventing or curing

Imperative for a Solution:Accelerating Impacts

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2015 2030 2050

46.8

74.7

131.5AD Patients

(Millions)

Alzheimer’s Disease International. World Alzheimer Report 2015. http://www.alz.co.uk/research/world-report-2015. Accessed February 2016

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• Dementia is financially debilitating for patients and their families.

• Dementia costs families nearly double the amount of other major diseases in the last 5 years of life.

• Treatment involves many out-of-pocket expenses that use, on average, almost one third of a patient’s wealth and impoverish about half of U.S./ W Eu dementia patients.

Impacts on Patients and FamiliesSource Time 2015, Annals of Internal Medicine 2015

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Drug Development in AD Last 20 years 101 negative Ph III trials…… success rate of 0.4 %

1993-2001 Approvals• 1993 Tacrine (Cognex)

first one approved now off market due to safety

• Nov 96 Aricept approved• 2000: Rivastigmine• 2001 Galantamine

2003 Approvals• Memantine

2006-2008 Failures• Serotonin 6 receptor

antagonists halted after phase 2

• Leuprolide • Tramiprosate• Flurizan

Other Failures• NSAID’s• Latrepirdine• Histamine H3 receptor

antagonists

2011-2012 Failures• Gamma secretases Semagacestat,

Avagacestat, Elan: AN1792• Amyloid immunoRx Bapineuzumab• Solanezumab (+/-)• Vaccination AD02• H3 receptor antagonist SAR 110894

2013-2014 Failures• Insuline path:

Rosiglitazone, Atorvastatin, Simvastatin

• Amyloid: Gantenerumab*, Crenezumab*

• Passive immunization: IVIG• Beta Secretase: LY2886721• ABT126 Nicotinic• PRX3140 Ser4 Rec and

terminated in AD

AcEi NMDA receptor

antagonists

2015 Failures• MAO-Bi

Sembragiline failed phase 2 on primary efficacy

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The Alzheimer's’ LandscapeCiteline Export, May 2016

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Why we need to continue trying and to succeed 35% of people age 60 or older are most afraid of developing Alzheimer’s Disease or dementia (cancer 23%)

Alzheimer’s Disease International. World Alzheimer Report 2015. http://www.alz.co.uk/research/world-report-2015. Accessed February 2016

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Current Dementia Drug Discovery Paradigm is Not Working

Challenges with dementia drug

discovery:1.Target Identification:

Complicated disease, poorly understood

2.Discovery and Development: The majority of dementia programs narrowly focus on amyloid beta and tau approaches

3.Clinical Development: High cost, complexity, risk, and length of clinical trials

Summary of AD Trials 2002-20121

1Quintiles database using internal de-identified data

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What are the Current Treatments?Limited in time and efficaciousness

On the market for almost 20 years

There are currently only symptomatic treatments available to patients:• T

hey do not modify the course of the disease, but provide short-term improvements to a patient and delay briefly putting a patient in an institution

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• Prodromal AD – before a patient has signs & symptoms of AD› Aged 50+› Episodic memory problems – where did you leave your keys?

• Where are these people?› At home, in the community.› No real symptoms› No-one self-identifies with potentially having a disease

• How to find them?› Advertising› Digital outreach› Public awareness

• What happens?› We get the “worried well”› We spend a lot of time & money screening for the “real” patients.

Now Let’s Look at Earlier Diagnosis

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2016 Modeling: Registry StatisticsExample of registry recruiting

On line 6,750,000 Registrants

675,000 Subjects Referred

27,000 Subjects Screened

22,500 Subjects Needed450

0 Subjects

Randomized

Online Registry• Demographics• Cognition testing online• Family History• 10 % referred to a site

Referral and Prescreening• BHR and Healthy Brains referred to sites• Only 4 % registrants get screened

Current Registry Status

• To recruit the estimated 4500 subjects in 2016,

• Nearly 7 million registry participants are needed

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The Continuum of AD and Normal Aging

TRIAL SUBJECT OF TODAY

TRIAL SUBJECT OF TOMORROW

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• The challenges:› Only trial drugs available› Very difficult to identify suitable patients› Aim is to prevent the disease developing or progressing

• Intervene earlier at the prodromal stage

• Innovative clinical trial design acceptable for regulators

• Optimal and pragmatic execution of studies: › Right study design with right duration› Acceptability of patients and caregiver of invasive procedures (CSF)› Decrease of inter-rater variability (certification of raters)

The Future: Early Intervention & DMDs

FIRST READ-OUT OF A POTENTIAL NEW THERAPY Q4 2016!!

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Young Subjects People Trial Elderly Subject Trial G7 EPAD

• Treatment of the children of AD people with a confirmed genetic mutation

• Tx with 2 experimental drugs & placebo

• Treating young people : 25 – 40 – who have no symptoms

• Biomarker outcome• NIH sponsored• Most high profile trial in AD in

the world• 10 countries, 30 sites, 240 pts

• Treatment of 5000+ healthy elderly subjects

• Biomarker positive : randomised to pioglitazone or placebo

• Biomarker negative : randomised to placebo

• Time to develop MCI• 7 countries, 63 sites 6,116 pts

• Pan- Eu initiative led by D Cameron and backed by the G7 countries

• 24,000 high risk subject virtual registry across Eu

• 6,000 extremely high risk subjects in a managed registry

• Up to 5 years longitudinal follow up : PET, MRI, Cognition

• 1000 subjects “trial-ready” at a given time point

• Adaptive design, I-Spy-type trial for such subjects

• 16 pharma companies

Leading ScienceFocus on Prevention

1Quintiles database & Clinical trials.gov