Therapeutic Advances:

What will impact the future treatment of Dementia?

Dementia: Issues Detection and Diagnosis

Late diagnosis, poor staging, low patient stratification and limited therapeutics

The diagnosis of neurological disease is too complex and far too late…

→ Multiple disparate data points used in diagnosis

→ Cognition tests, MR, PET, IVD, HER, Sleep, Smell,

→ Few collected and aggregated in a meaningful way

→ Diagnosis based on clinical symptoms not disease mechanism

→ Late diagnosis

→ Limited patient stratification→ Unclear patient staging→ Lack of “disease quantification”→ Limited treatment selection

guidance → Selection for clinical trials

usually inaccurate

→ Few therapies available→ Clinical trial success in

neurology (aside from select indications) has been low due to poor disease understanding and patient identification and staging

Dementia: Future Treatments

x Baxter - mAb - Gammagardx Lilly – mAb – Solanezumabx J&J – mAb - Bapineuzumabx Roche – mAb – Gantenerumabx Lilly - β-Secretase inhibitor - LY2886721 (liver toxicity)

• Biogen – mAb – Aducanumab ph2• Lilly – mAb – Solanezumab / AZD3293• Roche - Gantenerumab / Crenezumab• Eisai - BAN2401 / E2609• Merck – MK8931 - Verubecestat

Earlier intervention :?Tx Efficacy

(2) MCI due to AD (mild symptoms but can still perform daily tasks)

(1) Preclinical Alzheimer’s disease (no outward symptoms but some early brain changes)

(3) dementia due to Alzheimer’s disease (pronounced symptoms that interfere with everyday tasks)

Temporal evolution of relative abnormality in Alzheimer’s disease markersJack CR et al. Lancet Neurol 2013;12:207–16. • Alzheimer’s Disease (AD) is

the most common form of Dementia

• Aβ deposition begins early, prior to the onset of cognitive decline

• Tau pathology is thought to appear next, along with neurodegeneration

• Uses

• Patient stratification• Disease staging• Progression marker

• Dementia develops after substantial neurodegeneration has already occurred

Genomics

Therapeutic Advances:

What will impact the future treatment of Dementia?

1. Dementia Issues Detection, Diagnosis, Treatment• Dr Ben Newton: Global Head - PET, Director Neurology, GE Healthcare Life

Sciences

2. Genetic Biomarkers for Early detection of Alzheimer’s Disease and Dementia Risk• Dr Richard Pither: CEO Cytox

3. Patient Non-Adherence and Challenges For Carers• Tom Blackburn PhD., DSc., HonFBPhS: Chair, British Pharmacological Society

Industry Committee

4. The Economics of Dementia Treatment and Reimbursement• Matthew Bending PhD, MSc, BSc Econ: Director, Head of HTA, Strategy &

Communication Real World Strategy and Analytics, Mapi Group

5. Panel Q&A

Genetic biomarkers for early detection of Alzheimer’s Disease and Dementia Risk

Dr Richard Pither, CEO

Cognitivetests

Brain imagingMRI/CT

Limitedtreatment

Subjective memorycomplaint

Watchfulwaiting

Alzheimer’s Disease and the need for early and accurate tests

Current diagnostic testing lacks accuracy No new treatments in 15 years Development of new drugs requires stratification of patients Treatment with new drugs will require early intervention and

targeting:-• Mechanism• Cost• Safety

global dementia 44m today, to treble by 2050 to 135m at a

cost of $600bn

Non-specific early symptoms can confound accurate diagnosis Active pathogenic mechanism precedes symptoms by many years A simple blood-based biomarker is needed….

Amyloid Plaque Neurofibrillary Tangle

Alzheimer’s Disease – challenges of early detection

Brain Amyloid ImagingPET – Positron Emission

Tomography

Lumbar PunctureCSF – amyloid and tau fragments

Alzheimer’s Disease and genetic risk

Professor John Hardy, UCL

ApoE GWAS CYTOX + Affymetrix

80%

60%

Genetic building block strategy: Polygenic Risk Score

variaTECTTM

Accu

racy

Existing New

SNPfitRTM

A polygenic risk score (PRS) algorithm is a sum of genetic risk1. Comprehensive AD SNP genotyping array2. Amyloid stratification PRS algorithm3. genoTOR PRS algorithm for identification of clinical AD risk

Genetics offers an opportunity for early identification of AD risk

• Assist Pharma companies in stratifying early subjects for clinical trials• Provide new tools to progress academic research• Provide a clinical test for physicians and their patients

Best in class genotyping platform (variaTECT) with one software solution offering two analysis options:-

1. Amyloid stratification PRS algorithm:

2. genoTOR PRS algorithm: 93%accuracy

83%accuracy

80%accuracy

to

Timing is right - prospects for AD treatment are improving

31st August 2016:-Trial shows tantalising signs that new Alzheimer's drug could benefit early-stage patients (Biogen –aducanumab; FDA fast-track review)

• No new drugs approved for Alzheimer’s Disease treatment in over 15 years• ~93 medicines in development in the United States• Growing pharma activity:-

• Eli Lilly: Solanezumab (EXPEDITION 3) – November 2016• Biogen: Aducanumab – FDA fast-track review• Merck: Verubecestat (EPOCH) – June 2017

Therapeutic Advances: What Will Impact Future Treatments of

Dementia and Alzheimer’s Disease

Title: Patient Non-Adherence and Challenges For Carers

Speaker: Tom Blackburn PhD., DSc., HonFBPhS

Chair, British Pharmacological Society Industry Committee

(Stream B, Moore 14.10 – 14.15)

Dementia now leading cause of death in 2015

There are many types of dementia. Alzheimer’s is the most common form

Number of deaths from top 5 leading causes 2015

England & Wales, ONS November 2016

Predictors for treatment non-adherence in patients with

Dementia & Alzheimer’s Disease

Brady & Weinman, Dementia Geriatr Cogn Disorders 2013, 35: 351-363

Five Key Challenges to Future Treatment of Dementia & Alzheimer’s

Disease

1. The brain is the human body’s most complicated organ2. There are multiple biochemical pathways and neuronal

circuits which lead to Dementia and Alzheimer’s disease, and likely requires a combination of treatments

3. Dementia & Alzheimer’s diagnoses tend to arrive decades after the onset of the disease

4. Clinical trial criteria and recruitment has proven exceptionally challenging

5. We need sensitive tools to measure early stages of Alzheimer’s disease and dementia

P A T I E N T - C E N T E R E D R E S E A R C H S E R V I C E S

Economics of Dementia Treatment and ReimbursementTherapeutic Advances: What will Impact Future Treatment of Dementia?

Dr. Matthew Bending, 1st December 2016, Genesis QEII Westminster, London

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Economic Considerations for new Dementia treatments

Clinical Development

Reimbursement & Patient access**Source: Pujolras L.M., Cairns J. Why do some countries approve a cancer drug and others don’t? Journal of Cancer Policy 4 (2015) 21–25

$1tn cost worldwide

by’18 $818bn cost worldwide>$5,000 per year cost of caring0.55 mean EQ-5D utility

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Health Technology Assessment of Dementia treatments

Source: Illustration based on Husereau, D; Henshall, C; Sampietro-Colom, L; Thomas, S. Changing health technology assessment paradigms? Int J Technol Assess Health Care. 2016 Oct 21:1-9. [Epub ahead of print]

HTA/ payer/ health system engagement

New approaches to scientific dialogues

(between HTA bodies, industry, regulators, providers, patients)

HTA influence on the pipeline/ priorities of

R&D

Use of adaptive/ lifecycle approaches to

technology management

Increasing need to use real-world data Improved

patient access to valuable

innovations

Integrated engagement

between Health Technology Assessment (HTA) , payer, regulatory

New approaches to scientific dialogues

between HTA bodies, industry, regulators, providers, patients

Early HTA influence

on the pipeline priorities of R&D

Use of adaptive lifecycle

approaches

Increasing need to use real-world

data HTA 2.0

Improved patient access to innovations

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Reimbursement – “Early” Integrated Scientific Advice

“To support manufacturers in optimising their product development programme to generate evidence that is relevant to regulators, HTA bodies and payers for timely patient access”

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Shifting Regulatory and HTA Paradigm

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Integrated – parallel & joint scientific advice

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Key Economic/HTA challenges in Dementia

Economic analysis

Economic Model conceptualisation Model conceptualisation for

Disease Modifying Therapy Key modelling assumptions

1

Comparators for economic model Relevant comparison in

practice Background treatments &

use of historical control data

3

Outcomes/HRQL Clinically meaningful

difference in practice Appropriate

HRQL/caregiver burden instrument

Innovative: ”mixed methods”

4

Evidence Synthesis/Review Incorporation of

observational studies Confounders & methods Resource use and costs

5

Population/Subgroups Trial population

inclusion/exclusion Subgroups (such as

severity of disease – AchE inhibitors)

2

Long-term extrapolation Extrapolation of new DMT

beyond study period (inparticular for early disease)

Appropriate incorporation of observational data to ensure early access

6

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AAR report for transformative medicines

Source: UK Government: Accelerated Access Review: Final Report Review of innovative medicines and medical technologies 24th October 2016. Pg. 31

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Future considerations for reimbursement

Early engagement key to ensure benefit and value is understood

Always consider Integrated Regulatory – HTA Scientific Advice

Patient engagement essential and important for early preparation

Collaboration, preparation and forward planning critical key for ensuring timely access for future DMT therapies in AD

Thank-you

Dr. Matthew Bending, Director, Head of HTA, Strategy & Communication, Mapi, RWSA

© Mapi 2016, All rights reserved

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Dr. Matthew W. Bending

Head of HTA, Strategy & Communication in Mapi RWS&A

PhD on topic of HTA influence on decision-making from University of York

>12 years consultancy experience in HTA strategy

Experience of some of the first early Integrated Scientific Advice (>30 to date)

Published in peer review journals & presented at international conferences on the topic

Current Treatment of Dementia & Alzheimer’s

DiseaseThe only treatments for the disease that have

so far been approved by regulatory authorities target specific neurotransmitter systems within the brain

Available medicines that ease symptoms of the disease and generally work for about six months, but generate combined annual sales of about $3 billion

It’s Too Late To Treat?