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Cognition Insight Briefing
© Defined Health, 2014 © Defined Health, 2014
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Addressing Cognitive Deficits Across CNS
Diso...
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Cognition Insight Briefing
© Defined Health, 2014
The information in this presentation has been obtained from what are b...
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Cognition Insight Briefing
© Defined Health, 2014
BioEurope Spring
March 10 – 12, 2014
Turin, Italy
www.therapeuticinsig...
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Cognition Insight Briefing
© Defined Health, 2014
Cognitive Impairment is a Prominent and Disabling Feature of Many
Diso...
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Cognition Insight Briefing
© Defined Health, 2014
Cognitive Dysfunction is Broad-Based and Meaningfully Affects Real-
Wo...
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Cognition Insight Briefing
© Defined Health, 2014
Cognition is a Highly Complex Construct
♦ Cognition is a suite of inte...
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Cognition Insight Briefing
© Defined Health, 2014
Attention
and/or
vigilance
Working
Memory
Executive
function
Episodic
...
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Cognition Insight Briefing
© Defined Health, 2014
Attention
and/or
vigilance
Working
Memory
Executive
function
Episodic
...
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Cognition Insight Briefing
© Defined Health, 2014
Attention
and/or
vigilance
Working
Memory
Executive
function
Episodic
...
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Cognition Insight Briefing
© Defined Health, 2014
Attention
and/or
vigilance
Working
Memory
Executive
function
Episodic...
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Cognition Insight Briefing
© Defined Health, 2014
Attention
and/or
vigilance
Working
Memory
Executive
function
Episodic...
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Cognition Insight Briefing
© Defined Health, 2014
Attention
and/or
vigilance
Working
Memory
Executive
function
Episodic...
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Cognition Insight Briefing
© Defined Health, 2014
Cognitive Impairment Ranges from a Defining Symptom to a Comorbidity
...
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Cognition Insight Briefing
© Defined Health, 2014
Well-Established, Large Markets Exist For Diseases Where Cognitive
Im...
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Cognition Insight Briefing
© Defined Health, 2014
The Pipeline is Heating Up for Diseases Where Cognition is a Core
Sym...
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Cognition Insight Briefing
© Defined Health, 2014
There is Increasing Interest in Comorbid (and Debilitating) Cognitive...
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Cognition Insight Briefing
© Defined Health, 2014
Brintellix is a New Multimodal Antidepressant that Also Addresses
Cog...
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Cognition Insight Briefing
© Defined Health, 2014
Lundbeck’s Brintellix scores well in new cognitive performance study
...
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Cognition Insight Briefing
© Defined Health, 2014
Lundbeck Rises to 2-Year High After Brintellix Cognition Study Result...
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Cognition Insight Briefing
© Defined Health, 2014
Attention
and/or
vigilance
Working
Memory
Executive
function
Episodic...
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Cognition Insight Briefing
© Defined Health, 2014
New Agents Will Need to Navigate a Complex Pattern of Crosstalk Among...
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Cognition Insight Briefing
© Defined Health, 2014
Countering Pathological Changes Underlying Cognitive Deficits
♦ Glyci...
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Cognition Insight Briefing
© Defined Health, 2014
Complementary Strategies to Address Cognitive Impairment
♦ Complement...
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Cognition Insight Briefing
© Defined Health, 2014
Cognitive Impairment: What are the Key Development Considerations?
Co...
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Cognition Insight Briefing
© Defined Health, 2014
The Right Patient? The MATRICS Program Defines Cognitive Impairment
A...
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Cognition Insight Briefing
© Defined Health, 2014
The Right Patient? Collaborative Efforts Aim to Define Cognitive
Impa...
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Cognition Insight Briefing
© Defined Health, 2014
The Right Measure? Consensus Development of Clinical Trial Endpoint
S...
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Cognition Insight Briefing
© Defined Health, 2014
The Right Measure? Consensus Endpoints Evolve Over Time
♦ Unfortunate...
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Cognition Insight Briefing
© Defined Health, 2014
The Right Measure? Competing/Alternative Endpoints Enter the Picture
...
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Cognition Insight Briefing
© Defined Health, 2014
Original Consensus Measures are Being Used in Ongoing Phase III Trial...
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Cognition Insight Briefing
© Defined Health, 2014
Can One Cognitive Test System Work for All Clinical Conditions?
♦ The...
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Cognition Insight Briefing
© Defined Health, 2014
The Right Time? Intervene Before the Damage is Done
Sfera, A. 2013, S...
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Cognition Insight Briefing
© Defined Health, 2014
The Right Time? Moving Earlier in AD
♦ Converging data from both gene...
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Cognition Insight Briefing
© Defined Health, 2014
The Right Time? Rethinking Schizophrenia as a Neurodevelopmental
Diso...
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Cognition Insight Briefing
© Defined Health, 2014
The Right Time? Cognitive Impairment is Evident at the Prodromal Stag...
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Cognition Insight Briefing
© Defined Health, 2014
The Right Time? Cognitive Dysfunction is Evident in Prodromal HD
TRAC...
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Cognition Insight Briefing
© Defined Health, 2014
The Right Time? Cognitive Dysfunction is Evident in Prodromal HD
www....
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Cognition Insight Briefing
© Defined Health, 2014
The Right Measure at the Right Time?
Cognitive Impairment: Pathway to...
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Cognition Insight Briefing
© Defined Health, 2014
Cognitive Impairment: What are the Key Commercial Considerations?
♦ I...
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Cognition Insight Briefing
© Defined Health, 2014
Indication Prioritization: Commercial (as well as Scientific and
Clin...
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Cognition Insight Briefing
© Defined Health, 2014
Establishing Value for Agents Addressing Cognitive Impairment
♦ Depen...
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Cognition Insight Briefing
© Defined Health, 2014
Documentation for the Burden/Cost Associated with Huntington’s
Diseas...
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Cognition Insight Briefing
© Defined Health, 2014
The Pipeline is Not Waiting
Prana Announces Successful Phase 2 Result...
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Cognition Insight Briefing
© Defined Health, 2014
Final Considerations
♦ It is critical to show that agents that addres...
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Cognition Insight Briefing
© Defined Health, 2014
BioEurope Spring
March 10 – 12, 2014
Turin, Italy
www.therapeuticinsi...
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Project XXXX TOPIC, DATE
© Defined Health, 2014
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Cognitive Impairment Across CNS Disorders 022014 webinar

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Cognitive Impairment Across CNS Disorders 022014 webinar

  1. 1. 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
  2. 2. 2 Cognition Insight Briefing © 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 information 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 addressee 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
  3. 3. 3 Cognition Insight Briefing © Defined Health, 2014 BioEurope Spring March 10 – 12, 2014 Turin, Italy www.therapeuticinsight.com Defined Health is pleased to present: Defined Health will also be participating in the following industry events: Cancer Progress by Defined Health March 4 - 5, 2014 | New York City | http://www.cancerprogressbyDH.com Therapeutic Insight by Defined Health at BIO-Europe Spring® March 10 - 12, 2014 | Turin, Italy | http://dfndhlth.com/BES-2014 Texas Life Science Forum | February 20, 2014 | Houston | http://dfndhlth.com/2014TexasLifeScienceForum The Healthcare Summit | February 21, 2014 | Houston | http://dfndhlth.com/HealthcareSummit AACR Annual Meeting | April 5 - 9, 2014 | San Diego | http://dfndhlth.com/AACR-2014 Israel Innovation Conference 2014 | May 20 - 22, 2014 | Tel Aviv Fairgrounds, Israel | http://dfndhlth.com/MIXiii-2014 ASGCT Annual Meeting | May 21 - 24, 2014 | Washington, D.C. | http://dfndhlth.com/ASGCT-2014 ASCO Annual Meeting | May 30 - June 3, 2014 | Chicago | http://dfndhlth.com/ASCO-2014 BIO International Convention 2014 | June 23 - 26, 2014 | San Diego, CA | http://dfndhlth.com/BIO-2014 BioPharm America™ 2014 | September 22 - 24, 2014 | Boston, MA | http://dfndhlth.com/BPA-2014 Licensing Executives Society Annual Meeting | October 5 - 8, 2014 | San Francisco | http://dfndhlth.com/LES-2014 ASH Annual Meeting | December 6 - 9, 2014 | San Francisco | http://dfndhlth.com/ASH-2014 25h Annual Cancer Progress Conference March 4 – 5, 2014 New York City www.cancerprogressbyDH.com
  4. 4. 4 Cognition 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 ADHD Schizophrenia Depression Parkinson’s Disease Multiple Sclerosis Autism Spectrum “Chemobrain” CABG Diabetes Lupus
  5. 5. 5 Cognition Insight Briefing © Defined Health, 2014 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
  6. 6. 6 Cognition Insight Briefing © Defined Health, 2014 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. Millan, M.J. et al. 2012 Nature Reviews Drug Discovery Nov., Vol. 11 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)
  7. 7. 7 Cognition Insight Briefing © Defined Health, 2014 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
  8. 8. 8 Cognition Insight Briefing © Defined Health, 2014 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 Adapted from Millan, M.J. et al. 2012 Nature Reviews Drug Discovery Nov., Vol. 11
  9. 9. 9 Cognition Insight Briefing © Defined Health, 2014 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 Adapted from Millan, M.J. et al. 2012 Nature Reviews Drug Discovery Nov., Vol. 11
  10. 10. 10 Cognition Insight Briefing © Defined Health, 2014 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 Adapted from Millan, M.J. et al. 2012 Nature Reviews Drug Discovery Nov., Vol. 11
  11. 11. 11 Cognition Insight Briefing © Defined Health, 2014 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 Adapted from Millan, M.J. et al. 2012 Nature Reviews Drug Discovery Nov., Vol. 11
  12. 12. 12 Cognition Insight Briefing © Defined Health, 2014 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 Adapted from Millan, M.J. et al. 2012 Nature Reviews Drug Discovery Nov., Vol. 11
  13. 13. 13 Cognition Insight Briefing © Defined Health, 2014 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).
  14. 14. 14 Cognition Insight Briefing © Defined Health, 2014 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
  15. 15. 15 Cognition Insight Briefing © Defined Health, 2014 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.
  16. 16. 16 Cognition Insight Briefing © Defined Health, 2014 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
  17. 17. 17 Cognition Insight Briefing © Defined Health, 2014 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
  18. 18. 18 Cognition Insight Briefing © Defined Health, 2014 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
  19. 19. 19 Cognition Insight Briefing © Defined Health, 2014 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
  20. 20. 20 Cognition Insight Briefing © Defined Health, 2014 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 Adapted from Millan, M.J. et al. 2012 Nature Reviews Drug Discovery Nov., Vol. 11 What’s Next For Brintellix?
  21. 21. 21 Cognition Insight Briefing © Defined Health, 2014 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 Millan, M.J. et al. 2012 Nature Reviews Drug Discovery Nov., Vol. 11
  22. 22. 22 Cognition Insight Briefing © Defined Health, 2014 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. Millan, M.J. et al. 2012 Nature Reviews Drug Discovery Nov., Vol. 11
  23. 23. 23 Cognition Insight Briefing © Defined Health, 2014 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. Millan, M.J. et al. 2012 Nature Reviews Drug Discovery Nov., Vol. 11
  24. 24. 24 Cognition Insight Briefing © Defined Health, 2014 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.
  25. 25. 25 Cognition Insight Briefing © Defined Health, 2014 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
  26. 26. 26 Cognition Insight Briefing © Defined Health, 2014 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.
  27. 27. 27 Cognition Insight Briefing © Defined Health, 2014 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
  28. 28. 28 Cognition Insight Briefing © Defined Health, 2014 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
  29. 29. 29 Cognition Insight Briefing © Defined Health, 2014 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:
  30. 30. 30 Cognition Insight Briefing © Defined Health, 2014 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)
  31. 31. 31 Cognition Insight Briefing © Defined Health, 2014 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. 32. 32 Cognition Insight Briefing © Defined Health, 2014 The Right Time? Intervene Before the Damage is Done Sfera, A. 2013, Schizophrenia Past, Present and Future, South Coast Clinical Trials
  33. 33. 33 Cognition Insight Briefing © Defined Health, 2014 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. 34. 34 Cognition Insight Briefing © Defined Health, 2014 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.
  35. 35. 35 Cognition Insight Briefing © Defined Health, 2014 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. 36. 36 Cognition Insight Briefing © Defined Health, 2014 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. 37. 37 Cognition Insight Briefing © Defined Health, 2014 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
  38. 38. 38 Cognition Insight Briefing © Defined Health, 2014 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. 39. 39 Cognition Insight Briefing © Defined Health, 2014 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
  40. 40. 40 Cognition Insight Briefing © Defined Health, 2014 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
  41. 41. 41 Cognition Insight Briefing © Defined Health, 2014 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
  42. 42. 42 Cognition Insight Briefing © Defined Health, 2014 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.
  43. 43. 43 Cognition Insight Briefing © Defined Health, 2014 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
  44. 44. 44 Cognition Insight Briefing © Defined Health, 2014 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.
  45. 45. 45 Cognition Insight Briefing © Defined Health, 2014 BioEurope Spring March 10 – 12, 2014 Turin, Italy www.therapeuticinsight.com Defined Health is pleased to present: Defined Health will also be participating in the following industry events: Cancer Progress by Defined Health March 4 - 5, 2014 | New York City | http://www.cancerprogressbyDH.com Therapeutic Insight by Defined Health at BIO-Europe Spring® March 10 - 12, 2014 | Turin, Italy | http://dfndhlth.com/BES-2014 Texas Life Science Forum | February 20, 2014 | Houston | http://dfndhlth.com/2014TexasLifeScienceForum The Healthcare Summit | February 21, 2014 | Houston | http://dfndhlth.com/HealthcareSummit AACR Annual Meeting | April 5 - 9, 2014 | San Diego | http://dfndhlth.com/AACR-2014 Israel Innovation Conference 2014 | May 20 - 22, 2014 | Tel Aviv Fairgrounds, Israel | http://dfndhlth.com/MIXiii-2014 ASGCT Annual Meeting | May 21 - 24, 2014 | Washington, D.C. | http://dfndhlth.com/ASGCT-2014 ASCO Annual Meeting | May 30 - June 3, 2014 | Chicago | http://dfndhlth.com/ASCO-2014 BIO International Convention 2014 | June 23 - 26, 2014 | San Diego, CA | http://dfndhlth.com/BIO-2014 BioPharm America™ 2014 | September 22 - 24, 2014 | Boston, MA | http://dfndhlth.com/BPA-2014 Licensing Executives Society Annual Meeting | October 5 - 8, 2014 | San Francisco | http://dfndhlth.com/LES-2014 ASH Annual Meeting | December 6 - 9, 2014 | San Francisco | http://dfndhlth.com/ASH-2014 25h Annual Cancer Progress Conference March 4 – 5, 2014 New York City www.cancerprogressbyDH.com
  46. 46. 46 Project XXXX TOPIC, DATE © Defined Health, 2014
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