Addressing Cognitive Deficits Across Disorders to Improve Outcomes

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Cognition Insight Briefing
© Defined Health, 2014 © Defined Health, 2014
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Addressing Cognitive Deficits Across CNS
Disorders:
Potential to Improve Overall Outcomes
and QoL
Ginger S. Johnson, PhD
Vice President
Defined Health
March 2014

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© Defined Health, 2014
The information in this presentation has been obtained from what are believed to be reliable
sources and has been verified whenever possible. Nevertheless, we cannot guarantee the
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Cognitive Impairment is a Prominent and Disabling Feature of Many
Disorders
♦ Cognitive deficits are prominent and disabling feature of many disorders, CNS and
non-CNS (e.g., chemobrain, CABG, diabetes).
Alzheimer’s
Disease
ADHD
Schizophrenia
Depression
Parkinson’s
Disease
Multiple
Sclerosis
Autism
Spectrum
“Chemobrain” CABG
Diabetes
Lupus

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Cognitive Dysfunction is Broad-Based and Meaningfully Affects Real-
World Functioning
♦ Cognitive deficits are common in CNS disorders, and multiple domains are usually
affected.
 Approximately 75–85% of schizophrenia patients report cognitive impairment that
affects function (e.g., skill acquisition in psychosocial rehabilitation treatment,
demonstration of ability to solve simulated interpersonal problems, and
community functioning).
 Cognitive dysfunction limits the professional and social options of autistic
individuals.
 In depression, cognitive impairment is persistent and strongly related to disability,
with recovery inversely correlated with the severity of deficits. Even in ostensibly
remitted patients, residual cognitive impairment compromises real-world
functioning and socio-professional efficacy.
 Cognitive deficits are prominent in even the euthymic phase of bipolar disorder,
and persistence during remission predicts poor long-term recovery.
 Cognitive impairment often affects personal life and vocational status in MS
patients.
 The debilitating cognitive deficits observed in ADHD often continue into adulthood.
Millan, M.J. et al. 2012 Nature Reviews Drug Discovery Nov., Vol. 11

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Cognition is a Highly Complex Construct
♦ Cognition is a suite of interrelated conscious (and unconscious) mental activities.
♦ Cognitive dysfunction does not just signify poor memory – the range of cognitive
impairment is broader or more complex.
Universal Domains:
• Attention, working memory, executive
function
• Procedural learning and memory
• Speed of processing
• Fear-extinction learning
• Semantic memory
Higher Domains:
• Episodic memory
• Social cognition
• Theory of mind
• Verbal learning and memory
• Language (use and understanding)

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Attention
and/or
vigilance
Working
Memory
Executive
function
Episodic
memory
Semantic
memory
Visual
memory
Verbal
memory
Fear
extinction
Processing
speed
Procedural
memory
Social
cognition
Language
Major
depression
+(+) ++ ++ ++ + + +(+) 0/+? ++(+) + +(+) +
Bipolar
disorder
++(+) ++ ++ ++ + + ++ +? ++ 0 ++ ++
Schizophrenia +++ +++ +++ +++ ++ +(+) +++ ++ ++ + +++ +++
ASD +++ + +++ ++ + + +(+) +(+) +++ 0/+ +++ +++
ADHD +++ ++ +++ 0/+ + ++ ++ + ++ + + 0/+
OCD +++(↑) +(+) ++ + 0/+ + 0/+ ++ ++ ++ + 0/+
PTSD +++(↑) +(+) +(+) ++ + + ++(+) +++ + 0 0/+ 0
Panic
disorder
+++(↑) + 0/+ + 0/+ 0/+ + ++ ++ 0 0 0
GAD + + 0 0 + + + + 0 0 0/+ 0
Parkinson’s
disease
++ ++(+) ++ + 0/+ + + 0? +++ +++ +(+) +(+)
Alzheimer’s
disease
+(+) +(+) +(+) +++ +++ +++ ++(+) 0? + + + ++
Different Cognitive Domains are Affected in Different Disorders …
Should We Approach Therapeutics from Disease or Domain Standpoint?
Adapted from Millan, M.J. et al. 2012 Nature Reviews Drug Discovery Nov., Vol. 11
COGNITIVE DOMAINS

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Attention
and/or
vigilance
Working
Memory
Executive
function
Episodic
memory
Semantic
memory
Visual
memory
Verbal
memory
Fear
extinction
Processing
speed
Procedural
memory
Social
cognition
Language
Major
depression
+(+) ++ ++ ++ + + +(+) +
Bipolar
disorder
++(+) ++ ++ ++ + + ++ ++
Schizophrenia +++ +++ +++ +++ ++ +(+) +++ +++
ASD +++ + +++ ++ + + +(+) +++
ADHD +++ ++ +++ 0/+ + ++ ++ 0/+
OCD +++(↑) +(+) ++ + 0/+ + 0/+ 0/+
PTSD +++(↑) +(+) +(+) ++ + + ++(+) 0
Panic
disorder
+++(↑) + 0/+ + 0/+ 0/+ + 0
GAD + + 0 0 + + + 0
Parkinson’s
disease
++ ++(+) ++ + 0/+ + + +(+)
Alzheimer’s
disease
+(+) +(+) +(+) +++ +++ +++ ++(+) ++
Alzheimer’s is Characterized by Poor Learning and Memory

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Attention
and/or
vigilance
Working
Memory
Executive
function
Episodic
memory
Semantic
memory
Visual
memory
Verbal
memory
Fear
extinction
Processing
speed
Procedural
memory
Social
cognition
Language
Major
depression
+(+) ++ ++ + +(+) ++(+)
Bipolar
disorder
++(+) ++ ++ + ++ ++
Schizophrenia +++ +++ +++ +(+) +++ ++
ASD +++ + +++ + +(+) +++
ADHD +++ ++ +++ ++ ++ ++
OCD +++(↑) +(+) ++ + 0/+ ++
PTSD +++(↑) +(+) +(+) + ++(+) +
Panic
disorder
+++(↑) + 0/+ 0/+ + ++
GAD + + 0 + + 0
Parkinson’s
disease
++ ++(+) ++ + + +++
Alzheimer’s
disease
+(+) +(+) +(+) +++ ++(+) +
Deficits in ADHD are Focused on Attention and Executive Function

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Attention
and/or
vigilance
Working
Memory
Executive
function
Episodic
memory
Semantic
memory
Visual
memory
Verbal
memory
Fear
extinction
Processing
speed
Procedural
memory
Social
cognition
Language
Major
depression
+(+) ++ ++ ++ + +(+) 0/+? ++(+) +(+) +
Bipolar
disorder
++(+) ++ ++ ++ + ++ +? ++ ++ ++
Schizophrenia +++ +++ +++ +++ ++ +++ ++ ++ +++ +++
ASD +++ + +++ ++ + +(+) +(+) +++ +++ +++
ADHD +++ ++ +++ 0/+ + ++ + ++ + 0/+
OCD +++(↑) +(+) ++ + 0/+ 0/+ ++ ++ + 0/+
PTSD +++(↑) +(+) +(+) ++ + ++(+) +++ + 0/+ 0
Panic
disorder
+++(↑) + 0/+ + 0/+ + ++ ++ 0 0
GAD + + 0 0 + + + 0 0/+ 0
Parkinson’s
disease
++ ++(+) ++ + 0/+ + 0? +++ +(+) +(+)
Alzheimer’s
disease
+(+) +(+) +(+) +++ +++ ++(+) 0? + + ++
Schizophrenia is Characterized by a Broad Pattern of Cognitive Deficits

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Attention
and/or
vigilance
Working
Memory
Executive
function
Episodic
memory
Semantic
memory
Visual
memory
Verbal
memory
Fear
extinction
Processing
speed
Procedural
memory
Social
cognition
Language
Major
depression
Bipolar
disorder
++(+) ++ ++ ++ + + ++ +? ++ 0 ++ ++
Schizophrenia +++ +++ +++ +++ ++ +(+) +++ ++ ++ + +++ +++
ASD +++ + +++ ++ + + +(+) +(+) +++ 0/+ +++ +++
ADHD +++ ++ +++ 0/+ + ++ ++ + ++ + + 0/+
OCD +++(↑) +(+) ++ + 0/+ + 0/+ ++ ++ ++ + 0/+
PTSD +++(↑) +(+) +(+) ++ + + ++(+) +++ + 0 0/+ 0
Panic
disorder
+++(↑) + 0/+ + 0/+ 0/+ + ++ ++ 0 0 0
GAD
Parkinson’s
disease
Alzheimer’s
disease
Attention/Vigilance is Altered (Depressed or Heightened) in Several
Disorders

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Attention
and/or
vigilance
Working
Memory
Executive
function
Episodic
memory
Semantic
memory
Visual
memory
Verbal
memory
Fear
extinction
Processing
speed
Procedural
memory
Social
cognition
Language
Major
depression
+(+) ++ ++ ++ + + +(+) 0/+? ++(+) + +(+) +
Bipolar
disorder
++(+) ++ ++ ++ + + ++ +? ++ 0 ++ ++
Schizophrenia +++ +++ +++ +++ ++ +(+) +++ ++ ++ + +++ +++
ASD +++ + +++ ++ + + +(+) +(+) +++ 0/+ +++ +++
ADHD +++ ++ +++ 0/+ + ++ ++ + ++ + + 0/+
OCD +++(↑) +(+) ++ + 0/+ + 0/+ ++ ++ ++ + 0/+
PTSD
Panic
disorder
GAD
Parkinson’s
disease
++ ++(+) ++ + 0/+ + + 0? +++ +++ +(+) +(+)
Alzheimer’s
disease
Impaired Executive Functions Such as Planning, Decision Making and
Problem Solving Impact Every Day Functioning

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Cognitive Impairment Ranges from a Defining Symptom to a Comorbidity
Cognition is a
Defining
Symptom
Defining
Symptom
Core
Symptom
1
Core
Symptom
3
Core
Symptom
2
Defining
Symptom
Comor-
bidity 1
Comor-
bidity 3
Comor-
bidity 2
♦ Deficits in cognitive function range from a defining symptom of the disease
(e.g., Alzheimer’s disease) to one of several core symptoms (e.g.,
schizophrenia) to a non-core, but common comorbid symptom (e.g.,
depression).

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Well-Established, Large Markets Exist For Diseases Where Cognitive
Impairment is a Defining Symptom
EvaluatePharma
Alzheimer’s Disease (AD)
♦ Currently available AD treatments provide symptomatic relief,
temporarily, but do not alter the underlying disease process.
♦ Despite marginal efficacy, acetylcholinesterase inhibitors
(AChEIs) remain the standard of care for early and moderate
AD patients, with Pfizer’s Aricept (and generic donepezil)
being the product of choice (~50% share of total Rx for
branded and generic versions in 2012; $3.5B WW sales at
peak WW in 2009).
♦ The worldwide AD market peaked at over $7 billion in 2010.
Attention Deficit Hyperactivity Disorder (ADHD)
♦ The current worldwide ADHD market is estimated at
$5 billion.
♦ Psychostimulants are the gold standard of therapy given their
solid response rate (85-90%).
♦ Non-stimulants (e.g., norepinephrine reuptake inhibitor,
Strattera and alpha 2A adrenergic receptor agonists) capture
only a small fraction of the WW market share.
♦ The inattentive (versus hyperactive) subtype of ADHD is a
particular area of unmet need.
Cognitive
Impairment
is a Defining
Symptom

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The Pipeline is Heating Up for Diseases Where Cognition is a Core
Symptom, but Not Addressed with Existing Therapy
Positive
Symptoms
Negative
Symptoms
Cognitive
Symptoms
Motor
Symptoms
Psychiatric
Symptoms
Cognitive
Symptoms
Schizophrenia
♦ Defined by 3 symptom domains: positive (e.g,
hallucinations, delusions), negative (e.g., lack
of affect) and cognitive (e.g., attention,
working memory).
♦ Antipsychotics do not address the cognitive
symptoms.
♦ There are multiple agents/MOA’s in
development to address cognitive
dysfunction in schizophrenia.
Huntington’s Disease (HD)
♦ Hallmark symptoms of HD are motor (e.g.
chorea), psychiatric and cognitive symptoms.
♦ There is only one agent approved for HD
(Xenazine), and it addresses only the motor
symptoms of the disease.
♦ Feb. 19, 2014 Prana Biotechnology announced
positive results for its Reach2HD P2 trial
investigating PBT2 (Metal-Protein Attenuating
Compound) as a treatment for HD.

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There is Increasing Interest in Comorbid (and Debilitating) Cognitive
Symptoms Across a Range of CNS Diseases
Front Neurol. 2012; 3: 88.; Minerva Med. 2012 Apr;103(2):73-96.
Parkinson’s Disease (PD)
♦ The relative risk of developing dementia in
Parkinson's disease is five times that of controls.
♦ Cognitive impairment is a 2014 priority area for
The Michael J. Fox Foundation for Parkinson’s
Research.
Multiple Sclerosis (MS)
♦ Cognitive impairment occurs in 40-65% of MS
patients.
♦ It is seen in the subclinical radiologically isolated
syndrome, clinically isolated syndrome, and all
phases of clinical MS.
Depression
♦ Cognitive symptoms are commonly associated
with major depressive disorder.
♦ Lundbeck recently announced that its new
antidepressant, Brintellix shows improvement in
several cognitive domains.
Defining
Symptom
Cognitive
Impairment
Comor-
bidity 3
Comor-
bidity 2

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Brintellix is a New Multimodal Antidepressant that Also Addresses
Cognitive Impairment
Lundbeck Investor & Analyst Presentation, Oct. 2013
Attention
and/or
vigilance
Working
Memory
Executive
function
Episodic
memory
Semantic
memory
Visual
memory
Verbal
memory
Fear
extinction
Processing
speed
Procedural
memory
Social
cognition
Language
Major
depression
+(+) ++ ++ ++ + + +(+) 0/+? ++(+) + +(+) +
5-HT receptor
1A
5-HT receptor
1B
5-HT receptor
1D
5-HT receptor 3
5-HT receptor 7
5-HT
transporter

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Lundbeck’s Brintellix scores well in new cognitive performance study
November 12, 2013
Danish CNS specialist Lundbeck (LUND: CO) has released results from FOCUS, a new study showing that Brintellix (vortioxetine) met
its primary endpoint in demonstrating superiority over placebo in a composite score of two tests, the Digit Symbol Substitution
Test (DSST) and Rey Auditory Verbal Learning Test (RAVLT), that measure cognitive function in adults with major
depression.
In this study, Brintellix was shown to improve measures of cognitive domains such as executive function, speed of processing
and attention. These data were presented at the Annual Meeting at the American College of Neuropsychopharmacology (ACNP).
FOCUS, a global, eight-week, randomized, double-blind, parallel-group, placebo-controlled, fixed-dose study evaluated the efficacy
of Brintellix on cognitive function and major depression across three arms in around 600 patients aged 18-65 with an acute episode
of major depression. Cognitive function was measured in a series of validated tests that assessed changes from baseline to week 8
on specific cognitive domains known to be impaired in major depression, including executive function, speed of processing,
attention and memory.
Statistically-significant effect
Brintellix 10mg and 20mg demonstrated a statistically-significant improvement in cognitive performance versus placebo (0.36 and
0.33 respectively, p<0.0001), as assessed by a composite score of two validated neuropsychological tests, DSST and RAVLT. The
improvement in cognitive performance was shown to include a direct effect of Brintellix and was not solely due to
improvement in depressive symptoms (MADRS score). The study also showed significant improvements in cognitive
symptoms for both Brintellix dosages assessed with a patient-reported outcome questionnaire (PDQ), which supports
the clinical relevance of the findings in the neuropsychological tests.
thepharmaletter.com
Brintellix Addresses Cognitive Domains Relevant to Depression

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Lundbeck Rises to 2-Year High After Brintellix Cognition Study Results
♦ Brintellix, approved in the U.S. and Europe 2013 to treat major depression, showed a
statistically significant improvement in cognitive function in a 600 patient study.
♦ Deutsche Bank AG analyst Tim Race raised his peak sales forecast to $1.85 billion in
2019 from $1.5 billion.
Bloomberg.com
Cognition Results

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Attention
and/or
vigilance
Working
Memory
Executive
function
Episodic
memory
Processing
speed
Major
depression
+(+) ++ ++ ++ ++(+)
Bipolar
disorder
++(+) ++ ++ ++ ++
Schizophrenia +++ +++ +++ +++ ++
ASD +++ + +++ ++ +++
ADHD +++ ++ +++ 0/+ ++
OCD +++(↑) +(+) ++ + ++
PTSD +++(↑) +(+) +(+) ++ +
Panic
disorder
+++(↑) + 0/+ + ++
GAD + + 0 0 0
Parkinson’s
disease
++ ++(+) ++ + +++
Alzheimer’s
disease
+(+) +(+) +(+) +++ +
♦ Next indication(s):
• ADHD?
– Big market
– Established clinical/regulatory
pathway
– Entrenched generic standard of
care
– Clear areas for differentiation
• Cognitive impairment in
schizophrenia or PD?
• Non-existent markets
• Evolving clinical/regulatory
pathway
• No competition
• Value proposition to be
defined
What’s Next For Brintellix?

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New Agents Will Need to Navigate a Complex Pattern of Crosstalk Among
the Cellular Mechanisms Influencing Cognitive Function
♦ There are two complementary
ways to restore cognitive
performance:
1) Countering pathological
changes underlying deficits
2) Recruiting pro-cognitive
mechanisms that are
independent of disease etiology

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Countering Pathological Changes Underlying Cognitive Deficits
♦ Glycine B agonists are designed to treat
schizophrenia by stimulating hypoactive NMDA
receptors localized on GABAergic interneurons
in the prefrontal cortex (PFC).
♦ The epigenetic developmental disorder Fragile X
syndrome is characterized by excessive
metabotropic glutamate receptor 5 (mGluR5)-
mediated LTD (long term depression of
neuronal synapses), which leads to cognitive
deficits that can be countered by mGluR5
antagonists at these sites.
♦ Although conceptually attractive, pathology-
driven approaches have limitations.
 They may only be applicable to a
subpopulation of patients.
 Molecular substrates underlying cognitive
deficits remain not generally well
understood.

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Complementary Strategies to Address Cognitive Impairment
♦ Complementary strategies for
symptomatic treatment do not attempt to
normalize a pathological change, such as
NMDA receptor hypofunction.
♦ Rather, they engage compensatory pro-
cognitive mechanisms spared by the
disorder in question. For example, there is
no evidence for 5-HT6 or histamine H3
receptor hyperactivation in schizophrenia,
yet antagonists hold promise for
correcting a range of cognitive deficits in
schizophrenia as well as in other disorders
such as Alzheimer’s and depression.
♦ Pathology-decoupled mechanisms may
actually have a broader application than
pathology-driven strategies.

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Cognitive Impairment: What are the Key Development Considerations?
Cognitive Impairment: Pathway to a Pipeline
♦ Right patient?
♦ Right measure?
♦ Right time?
♦ Let’s assume we have the right target.

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The Right Patient? The MATRICS Program Defines Cognitive Impairment
Associated with Schizophrenia (CIAS)
♦ The MATRICS* group determined seven separable cognitive domains that are
affected in schizophrenia.
Cognitive
Deficits in
Schizophrenia
Verbal
fluency
Attention/
Vigilance
Visual
learning/
Memory
Verbal
learning/
Memory
Social
learning
Working
memory
Reasoning/
Problem
solving
Sellin, A.K., et. al. 2008 CNS Sectr. Vol 13, Nov 11
*MATRICS = Measurement and Treatment
Research to Improve Cognition in Schizophrenia
Characteristics of cognitive
impairment associated with
schizophrenia (CIAS):
• Highly prevalent
• IQ 1-2 SDs below normal
• Distinct from negative symptoms
• Precedes first clinical episode
• Persistent
• Long-term disability
• Non-progressive

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The Right Patient? Collaborative Efforts Aim to Define Cognitive
Impairment in Parkinson’s Disease
♦ The Michael J. Fox Foundation has supported research focused on Parkinson's
disease-related cognitive dysfunction and mood disorders, including efforts to better
define cognitive phenotypes of the disease. Major efforts in this area include:
 Partnering with the International Parkinson and Movement Disorder Society to
validate the diagnostic criteria for mild cognitive impairment in PD.
 Sponsoring a Phase I clinical trial to test a novel drug therapy for cognitive
impairment, as part of a landmark partnership with the pharmaceutical company
Sanofi.
 Supporting a comparative study of cognitive scales to determine which are the
most sensitive for measuring decline and response to treatment.
 Funding additional projects that seek to determine the neuropathological and
neurophysiological changes associated with cognitive dysfunction.

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The Right Measure? Consensus Development of Clinical Trial Endpoint
Specific for the Disease in Which Cognition is Impaired
♦ After identifying the cognitive domains that best characterized schizophrenia, the
MATRICS initiative devised a neuropsychological consensus cognitive battery to support
the discovery, clinical assessment and registration of new agents (MCCB = MATRICS
Consensus Cognitive Battery).
http://www.matricsinc.org/MCCB.htm

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The Right Measure? Consensus Endpoints Evolve Over Time
♦ Unfortunately, in various trials of compounds to treat CIAS, issues and limitations
associated with the MCCB have been discovered.
♦ These ‘limitations’ are now being addressed and revisions to the MCCB are under
consideration.
Issues Associated with the MCCB
 Training effects (can mask potential
treatment effect)
 Time consuming (full battery takes 60-
90 minutes to complete
 Requires highly specialized
administration and test scoring
 Selection criteria for the tests
apparently did not include established
drug sensitivity
Wesnes, K.A. and Edgar, C.J. Current Opinion in Pharmacology 2014, 14:62–73

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The Right Measure? Competing/Alternative Endpoints Enter the Picture
♦ Fully computerized batteries now commercially available offer alternative ways to operationalize
(i.e., define the measurement of the phenomenon) CIAS (versus the MCCB).
♦ A Pfizer-funded study comparing these tests showed that correlations between the computerized
batteries and the MCCB at the composite level were fairly high and the correlations observed at
the domain level were more modest.
♦ The correlations among the 7 domains on the 3 batteries varied greatly.
Stewart, M. 2009 Pfizer Global Research & Development, International Congress on Schizophrenia Research, San Diego, CA, USA, March 28-April 1, 2009
MCCB DOMAIN CORRELATIONS
SOP = Speed of processing; ATTN = Attention; WKMEM = Working
memory; VERL = Verbal learning; VISL = Visual learning; REAS = Reasoning; SOC = Social cognition
CNS VITAL SIGNS DOMAIN CORRELATIONS COGSTATE DOMAIN CORRELATIONS
Cogstate – Fully computerized cognitive battery
CNS Vital Signs – Fully computerized cognitive battery
Other measures used in these analyses:

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Original Consensus Measures are Being Used in Ongoing Phase III Trials
of CIAS: EVP-6124 (Encenicline)
♦ EVP-6124 is a selective, potent, brain penetrant oral compound that enhances
synaptic transmission in the brain and acts as a co-agonist in combination with
Acetylcholine (ACh) to enhance cognition. By sensitizing the alpha-7 receptor, EVP-
6124 makes it possible for smaller amounts of naturally occurring ACh to be effective
in activating the A7 receptor.
Clinicaltrials.gov
Phase Number of
Patients
Trial
Duration
Primary Endpoints Secondary Endpoints
IIb 150 12 wks • CogState battery • Schizophrenia Cognition
Rating Scale (SCoRS)
Interviewer Rating.
• Positive and Negative
Symptoms Scale (PANSS)
III (2) 700 26 wks • MCCB
• Schizophrenia Cognition
Rating Scale (SCoRS)
• PANSS
• Clinical Global Impression –
Severity (CGI-S)
• Clinical Global Impression –
Change scale (CGI-C)
• Quality of life, using the
EuroQoL-5D™ (EQ-5D)

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Can One Cognitive Test System Work for All Clinical Conditions?
♦ The Bracket CDR system is a fully computerized battery of cognitive tests
that assesses the major domains of cognitive function that are vulnerable to
aging, fatigue, disease, pathology, trauma, diet and pharmaceuticals.
Poster presentation at the ISCTM 9th Annual Scientific Meeting 19-21 February 2013, Washington DC, USA
↑= statistically significant enhancement
↔ = no significant change
↓= significant impairment
Empty box = domain not assessed
ATT & IP = Attention & Information Processing
WM & EF = Working Memory &/or Executive Function
EM / LTM= Episodic Memory / Long-Term Memory

32
The Right Time? Intervene Before the Damage is Done
Sfera, A. 2013, Schizophrenia Past, Present and Future, South Coast Clinical Trials

33
The Right Time? Moving Earlier in AD
♦ Converging data from both genetic at-risk and age at-risk cohorts suggest that the
pathophysiological process of AD begins as early as two decades prior to dementia.
♦ There have been multiple trial failures at the stage of mild to moderate dementia with
anti-Aβ therapies, despite evidence of biological activity, suggesting that interventions is
too late in the disease process.
http://alzheimer.wustl.edu/education/berg/berg2012/Slides/Sperling.pdf; Pillai, J.A., Cummings, J.L. (2013) Med Clin N Am 97;
http://www.earlysymptomsalzheimers.com/treatment#sthash.Yjf4SpLU.dpuf presentation
♦ Given the current understanding that the
greatest benefit is likely achieved by early
intervention, the focus of AD clinical trials has
shifted to the earliest stages of the disease.
♦ In April 2011, new international guidelines on
the diagnosis of AD were published that
specifically address diagnosis of AD in its
earliest stages, and mark a major change in
how experts think about and study AD,
including the need to incorporate biomarkers.

34
The Right Time? Rethinking Schizophrenia as a Neurodevelopmental
Disorder with Psychosis as a Late Stage of the Illness
♦ Although schizophrenic psychosis
usually emerges between ages 18-25,
several longitudinal population-based
studies indicate that problems are
evident much earlier.
♦ The trajectory of cognitive
development in children developing
schizophrenia could include reduced
elaboration of inhibitory pathways and
excessive pruning of excitatory
pathways leading to altered
excitatory–inhibitory balance in the
prefrontal cortex. Reduced
myelination would alter connectivity.
Insel TR. Rethinking Schizophrenia. Nature. 2010 Nov 11; ;468(7321):187-93.

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The Right Time? Cognitive Impairment is Evident at the Prodromal Stage
of Schizophrenia
♦ Four stages of schizophrenia are
hypothesized, from risk to
prodrome to psychosis to chronic
disability.
♦ With the advent of biomarkers
and new cognitive tools as well
as the identification of subtle
clinical features, we are
beginning to detect earlier
stages of risk and prodrome.
♦ Optimally, early interventions
with cognitive therapy may
enhance later-stage
employment, social inclusion
and function in the community.
Insel TR. Rethinking Schizophrenia. Nature. 2010 Nov 11; ;468(7321):187-93.
STAGE I STAGE II STAGE III STAGE IV
Pre-
symptomatic
Risk
Pre-psychotic
Prodrome
Acute Psychosis Chronic Illness
Features Genetic
vulnerability,
Environmental
Exposure
Cognitive,
behavioral, social
deficits; seeking help
Abnormal
thought and
behavior,
remitting-
relapsing course
Loss of function,
medical
complications,
incarceration
Diagnosis Genetic
sequence,
family history
SIPS, cognitive
assessment, imaging
Clinical
interview, loss
of insight
Clinical
interview, loss
of function
Disability None, mild
cognitive deficit
Change in school and
social function
Acute loss of
function, acute
family distress
Chronic
disability,
unemployment,
homelessness
Intervention Unknown Cognitive training?
PUFA?, Family
support?
Medication,
Psychosocial
interventions
Medication,
psychosocial
interventions,
rehabilitation
services
Stages of Schizophrenia

36
The Right Time? Cognitive Dysfunction is Evident in Prodromal HD
TRACK-HD Study (A longitudinal observational study)
 TRACK-HD is a multi-centre, multi-national prospective, observational biomarker study of
premanifest and early stage HD with no experimental treatment.
Objectives: determine what combination of measures is the most sensitive for detecting change
over the natural course of premanifest and early HD to validate these as potential outcome
measures for use in future therapeutic trials
 Subjects (n~360) were recruited from Canada, France, UK, Netherlands
 Participants were thoroughly examined every year for 3 years
 Dozens of measurements were made on each subject that included:
− Neuroimaging (MRI of brain)
− Motor symptoms (including high tech eye movement tracking
− Intellectual (cognitive) function
− Emotional well being
♦ Subjects without symptoms of HD (but gene carriers) were divided into two groups: those who were
estimated to be close to or far from disease onset:
 Predicting how close subjects were to onset was based on a mathematical calculation that used #
CAG repeats and age.
 A group of subjects in the early stages of HD and a control population that didn’t carry the gene
were also studied
www.thelancet.com/neurology Vol12 July 2013; Sanchez-Ramos, J. 2013 Cognition and Huntington’s Disease:HD 101, Huntington’s Disease Society of America

37
The Right Time? Cognitive Dysfunction is Evident in Prodromal HD
www.thelancet.com/neurology Vol12 July 2013; Sanchez-Ramos, J. 2013 Cognition and Huntington’s Disease:HD 101, Huntington’s Disease Society of America
• Symbol Digit Modalities Test
(SDMT) is a test of
visuomotorintegration,
measuring visual attention and
motor speed
• Stroop Test -word reading
condition is a test of processing
speed (subject must read as
many words as possible in 45
seconds from a list of the
names of colors printed in
black ink and the number of
words read correctly is the
primary variable).
• Circle Tracing –subject traces a
circle as quickly and accurately
as possible, aiming to stay
within the ring, using a stylus
on the horizontally-placed
tablet PC
Cognitive Assessments in the TRACK-HD Study

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The Right Measure at the Right Time?
Cognitive Impairment: Pathway to a Pipeline
♦ Right measure?
♦ As we target earlier in the disease, we have to ask again, is this the right measure?

39
Cognitive Impairment: What are the Key Commercial Considerations?
♦ Indication prioritization and sequencing (e.g., one agent/mechanism in dev
for cognitive impairment schizophrenia, Alzheimer’s and ADHD).
 Level of unmet need?
 Target patient population?
 Future Competitive Environment?
 Size of opportunity?
 Target prescriber base and educational requirements?
− Condition recognized? diagnosed? assessed? By whom?
♦ Establishing value
 Functional outcomes
 QALY/DALY values assigned to cognitive impairment
 Documentation

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Indication Prioritization: Commercial (as well as Scientific and
Clinical/Regulatory) Considerations
Category Subcategory Rating Rating Criteria WORST CASE SCENARIO BEST CASE SCENARIO
Scientific
Rationale
Clinical data 1-5 Evidence for target MOA in humans 1= Not validated in humans 5= Validated in a P3 human study
Preclinical data 1-5 Evidence for target MOA in animals or cell lines 1= Not validated in animals or cell lines 5= Validated in animals or cell lines
Unmet Needs
Disease severity 1-5 Impact on lifespan and quality of life 1 = Minor impact on QOL 5 = Always fatal
Efficacy 1-5 Efficacy of current treatment options 1 = Satisfactory 5 = Highly unsatisfactory
Safety 1-5 Safety of current treatment options 1 = Satisfactory 5 = Highly unsatisfactory
Competitive
Environment
Current
competition
1-5 Number of current competitors in space 1 = Significant number of competitors 5 = Limited
Pipeline 1-5
Transformational potential of newly launched
agents or clinical development pipeline
1 = availability or advanced development of
potential paradigm shifting therapy
5 = little or no competitive threat to
satisfy unmet needs
Clinical &
Regulatory
Current disease
understanding
1-5
Understanding—Is the disease pathophysiology
understood; are targets identified and validated?
1= low 5 = high
Preclinical burden 1-5
Availability of established Preclinical models and
biomarkers to study efficacy
1 = not established 5= well established
Clinical hurdle 1-5
(a) clarity of development path, (b) patient
recruitment difficulty, (c) time course of disease,
1 = prior failures, trials difficult to recruit,
long time course of disease
5 = POC well established, easy to
recruit trials short time course of
disease
Regulatory Path 1-5 Registration path is well established 1 = high regulatory hurdle 5 = low regulatory hurdle
Commercial
Attractiveness
Size of target
patient population
1-3 1 = 2 = 3 =
Reimbursement 1-3 Possibility of premium pricing 1= No 2= Maybe 3 = Yes
Investment for
POC study
1-3
Qualitative measure of investment required to
conduct early POC trial based on size and duration
1= Large investment
required
2 = Moderate investment
required
3 = Small investment
required
Overall financial
opportunity
1-3
Value proposition (of a transformational agent
versus SOC)
1 = Likely Low (<$500M) 2 = ≥$500M ˂$1B 3 = ≥$1B

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Establishing Value for Agents Addressing Cognitive Impairment
♦ Depending on this disorder, there are varied levels of support (studies, documentation)
with respect to the value of interventions addressing cognition.
AD
Prodromal AD
Cog in HD
Cog in PD
Cog in SZ
Size of Patient Population
StrengthofDocumentation

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Documentation for the Burden/Cost Associated with Huntington’s
Disease Cognitive Impairment is Lacking
♦ In HD, motor symptoms are associated with robust documentation in terms of impact
on quality of life and functional outcomes.
♦ Cognitive impairment is recognized as the most significant unmet need; however,
cognitive symptoms are not yet recognized by the payers in terms of impact on
burden of disease, as reflected in the text from the HD Parity Act of 2011 below.
S. 648: Huntington’s Disease Parity Act of 2011
Despite significant advances in medicine and a greater understanding of Huntington’s Disease,
the Social Security Administration has not comprehensively revised its rules for the medical
evaluation of neurological disabilities since 1985. The designation of this disease by the Social
Security Administration as ‘Huntington’s Chorea’ is both outdated and medically inaccurate, as
this term fails to recognize the behavioral and cognitive impact of Huntington’s Disease, while
also providing an incomplete characterization of the full spectrum of Huntington’s Disease for
purposes of Social Security Disability Insurance and the Medicare program.

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The Pipeline is Not Waiting
Prana Announces Successful Phase 2 Results in Huntington Disease Trial
February 18, 2014
Prana Biotechnology (ASX:PBT / NASDAQ:PRAN) has today announced the results of its Reach2HD Phase
2 clinical trial investigating PBT2 as a treatment for Huntington disease. The double-blind, placebo-
controlled study was conducted by the Huntington Study Group at research sites in the United States
and Australia. The study enrolled 109 individuals with Huntington disease who were randomly assigned
to receive daily doses of either PBT2 250mg, PBT2 100mg, or placebo for 26 weeks.
Key Points:
♦ Primary endpoints of safety and tolerability met.
♦ Secondary endpoint: Statistically significant improvement in a measure of executive function
(cognition) in research participants administered 250mg PBT2 daily (p=0.042).
♦ PBT2 250mg was also associated with a favorable signal in functional capacity.
♦ Preliminary evidence suggests PBT2 250mg reduced atrophy of brain tissue in areas affected in
Huntington disease, seen in a pilot imaging sub-study.
♦ Company plans to advance PBT2 to a confirmatory Phase 3 clinical trial.
PBT2 is also in P2 (The IMAGINE Trial) for the assessment of safety and tolerability, and effect on
amyloid deposition in the brains of patients with prodromal or mild Alzheimer’s disease.
http://pranabio.com/news/prana-announces-successful-phase-2-results-huntington-disease-trial

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Final Considerations
♦ It is critical to show that agents that address cognitive impairment results
in a meaningful and relevant improvement in real-world function and
quality of life.
♦ To establish value, trials must address the right patient (clearly defined
and diagnosable unmet need), at the right time in the progression of the
disease.
♦ In addition, the relevant cognitive domain(s) must be targeted and
measured.
♦ For diseases in which the diminished value on function and/or quality of
life, as well as cost burden, specifically attributable to cognitive
impairment has not been adequately established and documented (to
the satisfaction of the payers), the biopharma company may need to lead
the charge.

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Addressing Cognitive Deficits Across Disorders to Improve Outcomes

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