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Addressing Cognitive Deficits Across CNS Disorders: Potential to Improve Overall Outcomes and QoL

Ginger S. Johnson, PhDVice PresidentDefined Health

February 2014

1Cognition Insight Briefing © Defined Health, 2014 © Defined Health, 2014 1

February 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 information contained herein as to accuracy or completeness All expressions of opinion areinformation contained herein as to accuracy or completeness. All expressions of opinion are the responsibility of Defined Health, and though current as of the date of this report, are subject to change. The opinions and information set forth herein are expressed solely for the benefit of the

dd d l f h ( ) f h h h d d h haddressee and only for the purpose(s) for which the report was produced. Without the prior written consent of Defined Health, this report may not be relied on in whole or in part for any other purpose or by any other person or entity, provided that this report may be disclosed where disclosure is required by law.This report may contain information provided by third parties such as Thomson Reuters, Springer, EvaluatePharma, Datamonitor, Informa Healthcare, IMS Health and others with a proprietary interest in the data provided herein. Please note that you are not permitted to redistribute any such third party information without consent from the originator company.

© Defined Health, 2014

2Cognition Insight Briefing © Defined Health, 2014

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

Schizophrenia

Depression

ADHD Diabetes

Parkinson’s

Multiple Sclerosis

Autism

Lupus

Parkinson s DiseaseSpectrum

“Chemobrain” CABG


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 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 ostensiblywith 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, d d d land 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.


g g

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 compleximpairment is broader or more complex.

Higher DomainsUniversal Domains:• Attention, working memory, executive

functionP d l l i d

Higher Domains:

• Episodic memory

• Social cognition• Procedural learning and memory• Speed of processing• Fear-extinction learning• Semantic memory

• Theory of mind

• Verbal learning and memory

• Semantic memory • Language (use and understanding)



Different Cognitive Domains are Affected in Different Disorders … Should We Approach Therapeutics from Disease or Domain Standpoint?

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

COGNITIVE DOMAINS

Major depression

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

Bipolar disorder

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

hi h iSchizophrenia +++ +++ +++ +++ ++ +(+) +++ ++ ++ + +++ +++

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

ADHD +++ ++ +++ 0/+ + ++ ++ + ++ + + 0/+

OCD +++(↑) +(+) ++ + 0/+ + 0/+ ++ ++ ++ + 0/+

PTSD +++(↑) +(+) +(+) ++ + + ++(+) +++ + 0 0/+ 0

Panicdisorder

+++(↑) + 0/+ + 0/+ 0/+ + ++ ++ 0 0 0

GAD + + 0 0 + + + + 0 0 0/+ 0

Parkinson’s disease

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

Alzheimer’s ( ) ( ) ( ) ( ) 0?


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

Adapted from Millan, M.J. et al. 2012 Nature Reviews Drug Discovery Nov., Vol. 11

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


Major +(+) ++ ++ ++ + + +(+) +

depression+(+) ++ ++ ++ + + +(+) +

Bipolar disorder

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

Schizophrenia +++ +++ +++ +++ ++ +(+) +++ +++

ASD +++ + +++ ++ + + +(+) +++

ADHD +++ ++ +++ 0/+ + ++ ++ 0/+

OCD +++(↑) +(+) ++ + 0/+ + 0/+ 0/+

PTSD +++(↑) +(+) +(+) ++ + + ++(+) 0

Panicdisorder

+++(↑) + 0/+ + 0/+ 0/+ + 0

GAD + + 0 0 + + + 0


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

Alzheimer’s disease

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


disease


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


Major +(+) ++ ++ + +(+) ++(+)

depression+(+) ++ ++ + +(+) ++(+)

Bipolar disorder

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

Schizophrenia +++ +++ +++ +(+) +++ ++

ASD +++ + +++ + +(+) +++

ADHD +++ ++ +++ ++ ++ ++

OCD +++(↑) +(+) ++ + 0/+ ++

PTSD +++(↑) +(+) +(+) + ++(+) +

Panicdisorder

+++(↑) + 0/+ 0/+ + ++

GAD + + 0 + + 0


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


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


disease


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


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

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

Bipolar disorder

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

Schizophrenia +++ +++ +++ +++ ++ +++ ++ ++ +++ +++

ASD +++ + +++ ++ + +(+) +(+) +++ +++ +++

ADHD +++ ++ +++ 0/+ + ++ + ++ + 0/+

OCD +++(↑) +(+) ++ + 0/+ 0/+ ++ ++ + 0/+

PTSD +++(↑) +(+) +(+) ++ + ++(+) +++ + 0/+ 0

Panicdisorder

+++(↑) + 0/+ + 0/+ + ++ ++ 0 0

GAD + + 0 0 + + + 0 0/+ 0


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


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


disease


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


jMajor depression

Bipolar disorder

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

Schizophrenia +++ +++ +++ +++ ++ +(+) +++ ++ ++ + +++ +++

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

ADHD +++ ++ +++ 0/+ + ++ ++ + ++ + + 0/+

OCD +++(↑) +(+) ++ + 0/+ + 0/+ ++ ++ ++ + 0/+

PTSD +++(↑) +(+) +(+) ++ + + ++(+) +++ + 0 0/+ 0

Panicdisorder

+++(↑) + 0/+ + 0/+ 0/+ + ++ ++ 0 0 0

GAD





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

Attention and/or

vigilance

Working Memory

Executive function

Episodic memory

Semantic memory

Visual memory

Verbal memory

Fear extinction

Processing speed

Procedural memory


jMajor depression

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

Bipolar disorder

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

Schizophrenia +++ +++ +++ +++ ++ +(+) +++ ++ ++ + +++ +++

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

ADHD +++ ++ +++ 0/+ + ++ ++ + ++ + + 0/+

OCD +++(↑) +(+) ++ + 0/+ + 0/+ ++ ++ ++ + 0/+

PTSD

Panicdisorder

GAD


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



disease


Cognitive Impairment Ranges from a Defining Symptom to a Comorbidity

♦ 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 gschizophrenia) to a non-core, but common comorbid symptom (e.g., depression).

Cognition is a Defining

Core Symptom

1

Core Symptom

2

Comor-bidity 1

Defining Symptom

Defining Symptom

Core Symptom

3

Defining Symptom

Comor-bidity 3

Comor-bidity 23


Well-Established, Large Markets Exist For Diseases Where Cognitive Impairment is a Defining Symptom

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♦ 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 atbranded 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)

Cognitive Impairment is a Defining 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%)

gSymptom

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


EvaluatePharma

♦ The inattentive (versus hyperactive) subtype of ADHD is a particular area of unmet need.

The Pipeline is Heating Up for Diseases Where Cognition is a Core Symptom, but Not Addressed with Existing Therapy

Schizophrenia♦ Defined by 3 symptom domains: positive (e.g,

hallucinations, delusions), negative (e.g., lack of affect) and cognitive (e g attention

Huntington’s Disease (HD)♦ Hallmark symptoms of HD are motor (e.g.

chorea), psychiatric and cognitive symptoms.♦ There is only one agent approved for HDof affect) and cognitive (e.g., attention,

working memory).♦ Antipsychotics do not address the cognitive

symptoms.♦ There are multiple agents/MOA’s in

♦ 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♦ There are multiple agents/MOA s in

development to address cognitive dysfunction in schizophrenia.

positive results for its Reach2HD P2 trial investigating PBT2 (Metal-Protein Attenuating Compound) as a treatment for HD.

PositiveSymptoms

Cognitive Symptoms

Motor Symptoms

Cognitive Symptoms

Negative Symptoms

Psychiatric Symptoms


There is Increasing Interest in Comorbid (and Debilitating) Cognitive Symptoms Across a Range of CNS Diseases

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♦ Cognitive impairment is a 2014 priority area for

The Michael J. Fox Foundation for Parkinson’s Research.

Multiple Sclerosis (MS)f

Cognitive Impairment

♦ Cognitive impairment occurs in 40-65% of MS patients.

♦ It is seen in the subclinical radiologically isolated syndrome, clinically isolated syndrome, and all

h f li i l S

Defining Symptom

phases of clinical MS.

Depression♦ Cognitive symptoms are commonly associated

with major depressive disorder.

y p

Comor-bidity 3

Comor-bidity 2

with major depressive disorder.♦ Lundbeck recently announced that its new

antidepressant, Brintellix shows improvement in several cognitive domains.


Front Neurol. 2012; 3: 88.; Minerva Med. 2012 Apr;103(2):73-96.

Brintellix is a New Multimodal Antidepressant that Also Addresses Cognitive Impairment

Attention and/or

vigilance

Working Memory

Executive function

Episodic memory

Semantic memory

Visual memory

Verbal memory

Fear extinction

Processing speed

Procedural memory


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

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

5-HT receptor 1A

5-HT receptor 1B

5-HT receptor 1D

5-HT transporter

5-HT receptor 3

5-HT receptor 7


Lundbeck Investor & Analyst Presentation, Oct. 2013

Brintellix Addresses Cognitive Domains Relevant to Depression

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) metDanish 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 p p gand 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 processingon 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. Theimprovement 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

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.

h k G l i i d hi k l f $ 8 billi i♦ Deutsche Bank AG analyst Tim Race raised his peak sales forecast to $1.85 billion in 2019 from $1.5 billion.

Cognition Results


Bloomberg.com

What’s Next For Brintellix?

Attention and/or

vigilance

Working Memory

Executive function

Episodic memory

Processing speed

Major d i

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

♦ Next indication(s):• ADHD?

Big marketdepression( ) ( )

Bipolar disorder

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

Schizophrenia +++ +++ +++ +++ ++

– Big market– Established clinical/regulatory

pathway– Entrenched generic standard of

ASD +++ + +++ ++ +++

ADHD +++ ++ +++ 0/+ ++

OCD +++(↑) +(+) ++ + ++

Entrenched generic standard of care

– Clear areas for differentiation• Cognitive impairment in OCD +++(↑) +(+) ++ + ++

PTSD +++(↑) +(+) +(+) ++ +

Panicdisorder

+++(↑) + 0/+ + ++

g pschizophrenia or PD?

• Non-existent markets• Evolving clinical/regulatory

GAD + + 0 0 0


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

Alzheimer’s +(+) +(+) +(+) +++ +

pathway• No competition• Value proposition to be

d fi d


disease+(+) +(+) +(+) +++ + defined


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:performance:

1) Countering pathological changes underlying deficits

2) Recruiting pro-cognitive mechanisms that are independent of disease etiologyindependent 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 interneuronsin the prefrontal cortex (PFC).

♦ The epigenetic developmental disorder Fragile X syndrome is characterized by excessive metabotropic glutamate receptor 5 (mGluR5)-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 sitesantagonists at these sites.

♦ Although conceptually attractive, pathology-driven approaches have limitations. They may only be applicable to a

b l ti f ti tsubpopulation 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 foryet 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.



Lack of Receptor Selectivity has Plagued the Development of Agents Addressing Cognitive Impairment♦ M1 receptor agonism is a well-validated mechanism of action for treating cognitive impairment

and a valuable pharmacological profile that the pharmaceutical industry has endeavored to create for decades.

♦ Heptares’ selective M1 agonist has recently entered clinical development.


Heptares company presentation

Cognitive Impairment: What are the Key Development Considerations?

♦ Let’s assume we have the right target.

Cognitive Impairment: Pathway to a Pipeline♦ Right patient?

♦ Right measure?

♦ Right time?


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.

Verbal fluency

Attention/Vigilance

Reasoning/Problem

Characteristics of cognitive impairment associated with

Cognitive Deficits in

S hi h i

Vigilance

Visual

solving impairment associated with schizophrenia (CIAS):• Highly prevalent• IQ 1-2 SDs below normal

Di ti t f ti tSchizophrenia Visual learning/Memory

Verbal

Working memory

• Distinct from negative symptoms• Precedes first clinical episode• Persistent• Long-term disability

N iVerbal learning/Memory

Social learning

*MATRICS = Measurement and Treatment Research to Improve Cognition in Schizophrenia

• Non-progressive


Sellin, A.K., et. al. 2008 CNS Sectr. Vol 13, Nov 11

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♦ 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 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 companyimpairment, 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 treatmentmost sensitive for measuring decline and response to treatment.

Funding additional projects that seek to determine the neuropathological and neurophysiological changes associated with cognitive dysfunction.


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 y, g g (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♦ 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)

Ti i (f ll b k 60 Time consuming (full battery takes 60-90 minutes to complete

Requires highly specialized administration and test scoringadministration 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 y p g p

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.

MCCB DOMAIN CORRELATIONS CNS VITAL SIGNS DOMAIN CORRELATIONS COGSTATE DOMAIN CORRELATIONS

SOP = Speed of processing; ATTN = Attention; WKMEM = WorkingCogstate – Fully computerized cognitive batteryCNS Vital Signs Fully computerized cognitive battery


Stewart, M. 2009 Pfizer Global Research & Development, International Congress on Schizophrenia Research, San Diego, CA, USA, March 28-April 1, 2009

p p g; ; gmemory; VERL = Verbal learning; VISL = Visual learning; REAS = Reasoning; SOC = Social cognitionCNS 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.

Phase Number of Trial Primary Endpoints Secondary EndpointsPatients Duration

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

R ti S l (SC RS)

• PANSS• Clinical Global Impression –

S it (CGI S)Rating Scale (SCoRS) Severity (CGI-S)• Clinical Global Impression –

Change scale (CGI-C)• Quality of life, using the

EuroQoL-5D™ (EQ-5D)


Clinicaltrials.gov

( )

EVP-6124 (Encenicline) is Also in Development for AD

♦ In a Phase 2b clinical trial, encenicline demonstrated statistically significant and clinically important improvement in cognition and clinical function compared to placebo in patients with mild to moderate Alzheimer’s disease. p p

♦ A Phase 3 program in AD (COGNITIVE AD) was initiated in Jan. 2014.


http://www.alzforum.org/news/conference-coverage/experimental-a7-agonist-meets-cognitive-and-clinical-endpoints

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.

↑= sta s cally significant enhancement ↔ = no significant change ↓= significant impairmentEmpty box = domain not assessed ATT & IP = Attention & Information Processing


Poster presentation at the ISCTM 9th Annual Scientific Meeting 19-21 February 2013, Washington DC, USA

WM & EF = Working Memory &/or Executive Function EM / LTM= Episodic Memory / Long-Term Memory

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.

♦ Th h b lti l t i l f il t th t f ild t d t d ti ith♦ 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.

♦ Given the current understanding that the♦ 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 g j ghow experts think about and study AD, including the need to incorporate biomarkers.


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

The Right Time? Rethinking Schizophrenia as a NeurodevelopmentalDisorder with Psychosis as a Late Stage of the Illness

♦ Although schizophrenic psychosis usually emerges between ages 18-25,

l l i di l l i b dseveral longitudinal population-based studies indicate that problems are evident much earlier.

♦ The trajectory of cognitive♦ 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 Reducedprefrontal 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

STAGE I STAGE II STAGE III STAGE IVPre- Pre-psychotic Acute Psychosis Chronic Illness

Stages of Schizophrenia

prodrome to psychosis to chronic disability.

♦ With the advent of biomarkers and new cognitive tools as well

symptomatic Risk

p yProdrome

y

Features Genetic vulnerability, Environmental Exposure

Cognitive, behavioral, social deficits; seeking help

Abnormal thought and behavior, remitting-

Loss of function, medical complications, incarcerationg

as the identification of subtle clinical features, we are beginning to detect earlier sta es of risk and prodrome

Exposure remittingrelapsing course

incarceration

Diagnosis Genetic sequence, family history

SIPS, cognitive assessment, imaging

Clinical interview, loss of insight

Clinical interview, loss of function

stages of risk and prodrome.♦ Optimally, early interventions

with cognitive therapy may enhance later-stage

Disability None, mild cognitive deficit

Change in school and social function

Acute loss of function, acute family distress

Chronic disability, unemployment, homelessness

enhance later stage employment, social inclusion and function in the community.

Intervention Unknown Cognitive training? PUFA?, Family support?

Medication, Psychosocial interventions

Medication, psychosocial interventions, rehabilitationservices


Insel TR. Rethinking Schizophrenia. Nature. 2010 Nov 11; ;468(7321):187-93.

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 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− 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 #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

The Right Time? Cognitive Dysfunction is Evident in Prodromal HD• Symbol Digit Modalities Test

(SDMT) is a test of visuomotorintegration, measuring visual attention and

Cognitive Assessments in the TRACK-HD Study

measuring visual attention and motor speed

• StroopTest -word reading condition is a test of processing speed (subject must read asspeed (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 ofblack ink and the number of words read correctly is the primary variable).

• Circle Tracing –subject traces a circle as quickly and accuratelycircle as quickly and accurately as possible, aiming to stay within the ring, using a stylus on the horizontally-placed tablet PC


www.thelancet.com/neurology Vol12 July 2013; Sanchez-Ramos, J. 2013 Cognition and Huntington’s Disease:HD 101, Huntington’s Disease Society of America

tablet PC

The Right Measure at the Right Time?

♦ As we target earlier in the disease, we have to ask again, is this the right measure?

Cognitive Impairment: Pathway to a Pipeline

♦ 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?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 Clinical data 1-5 Evidence for target MOA in humans 1= Not validated in humans 5= Validated in a P3 human study

Rationale 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

Current 1 5 Number of current competitors in space 1 = Significant number of competitors 5 = Limited

Competitive Environment

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

Current disease understanding

1-5 Understanding—Is the disease pathophysiologyunderstood; are targets identified and validated? 1= low 5 = high

A il bilit f t bli h d P li i l d l dClinical & Regulatory

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

Size of target

CommercialAttractiveness

gpatient 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 duration1= Large investment required

2 = Moderate investment required

3 = Small investment required

Overall financial i

1-3 Value proposition (of a transformational agent versus SOC) 1 = Likely Low (<$500M) 2 = ≥$500M ˂$1B 3 = ≥$1B


Defined Health

opportunity versus SOC)

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.

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Size of Patient Population

Globally, Health Systems are Implementing Value-Based Pricing Models That in Many Cases Include Pharmaceuticals

In FY 2013, an estimated $850 million will be allocated to hospitals based on their overall performance on a set of quality measures that have been shown to improve clinical processes of

Implementation of Value-Based Pricing in Leading Health Systems

performance on a set of quality measures that have been shown to improve clinical processes of care and patient satisfaction. This funding will be taken from what Medicare otherwise would have spent, and the size of the fund will gradually increase over time, resulting in a shift from payments based on volume to payments based on performance1

G tl h d it i b t t t l b d i i t A hi iGermany recently changed its reimbursement system to a value-based pricing system. Achieving value will result in obtaining premium price, and not achieving value will result in a price based on similarly effective pharmaceuticals

Beginning 2014, the UK will engage in universal value-base pricing. They will begin with a basic threshold, expressed as cost per QALY, and then include three factors: 1) Burden of illness, 2) innovation and, 3) wider societal benefit

Th A li Ph i l B fi P i i A h i (PBPA) i f lThe Australian Pharmaceuticals Benefits Pricing Authority (PBPA) is now more frequently suggesting alternative pricing agreements in negotiations with pharma companies. As of June 2010, there were 90 alternative pricing agreements, including value-based, either in place or in development2


Compass Strategic Consulting1http://www.hhs.gov/news/press/2011pres/04/20110429a.html 2Deloitte Issue Brief: Value-based pricing for pharmaceuticals: Implications of the shift from volume to value 09/2012, http://deloitte.wsj.com/cfo/files/2012/09/ValueBasedPricingPharma.pdf

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 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

f S i l S i Di bili I d h M dipurposes of Social Security Disability Insurance and the Medicare program.


The Pipeline is Not Waiting

Prana Announces Successful Phase 2 Results in Huntington Disease TrialFebruary 18, 2014Prana Biotechnology (ASX:PBT / NASDAQ:PRAN) has today announced the results of its Reach2HD PhasePrana 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).( g ) p p g y (p )♦ 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♦ 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

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

li f lifquality 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 theand 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 cognitivelife, 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 cns disorders ... · ♦ the worldwide ad market peaked at...

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