Cognitive Impairment Across CNS Disorders 022014 webinar

1 Cognition Insight Briefing © Defined Health, 2014

© Defined Health, 2014 1

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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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


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


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)


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


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


++ ++(+) ++ + 0/+ + + +(+)


+(+) +(+) +(+) +++ +++ +++ ++(+) ++

Alzheimer’s is Characterized by Poor Learning and Memory



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


++ ++(+) ++ + + +++


+(+) +(+) +(+) +++ ++(+) +

Deficits in ADHD are Focused on Attention and Executive Function



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


++ ++(+) ++ + 0/+ + 0? +++ +(+) +(+)


+(+) +(+) +(+) +++ +++ ++(+) 0? + + ++

Schizophrenia is Characterized by a Broad Pattern of Cognitive Deficits



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



Attention/Vigilance is Altered (Depressed or Heightened) in Several Disorders



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


++ ++(+) ++ + 0/+ + + 0? +++ +++ +(+) +(+)


Impaired Executive Functions Such as Planning, Decision Making and Problem Solving Impact Every Day Functioning



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).


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


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.


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


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

http://us.brintellix.com/


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


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


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


++ ++(+) ++ + +++


+(+) +(+) +(+) +++ +

♦ 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?


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



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.



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.



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.


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


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.

https://www.michaeljfox.org/


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


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


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:


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)


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

http://www.bracketglobal.com/


The Right Time? Intervene Before the Damage is Done

Sfera, A. 2013, Schizophrenia Past, Present and Future, South Coast Clinical Trials


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.


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.


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


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

http://www.track-hd.net/


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


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?


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


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


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

Stre

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f D

ocu

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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.


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

http://pranabio.com/


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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Cognitive Impairment Across CNS Disorders 022014 webinar

Health & Medicine

Transcript of Cognitive Impairment Across CNS Disorders 022014 webinar