Steven J. Romano, MD Senior Vice President Medicines Development, Pfizer

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1 A Return to Rational CNS Drug Development: De-risking P3 Investments through Rigorous Early Phase Drug Evaluation ISCTM Autumn Scientific Meeting, October 1, 2013 Steven J. Romano, MD Senior Vice President Medicines Development, Pfizer

2 Disclosure/Conflict of Interest Statement Full-time employee of Pfizer, Inc

3 Key Points Drug development is a risky and costly business R&D productivity decreased through 2000 s Investment shifting to areas of greatest need Novel targets/mechanisms carry greater risk Need to better understand human biology of CNS conditions to advance innovative therapies Critical to adhere to rigorous drug development methodology (POM, dose selection, POC)

4 Developing New Medicines is a Risky, and Costly, Business Millions of Compounds Screened Preclinical Pharmacology Preclinical Safety Clinical Pharmacology & Safety High Risk Process years, $800MM+ <1 in 10 entering P1 becomes a medicine Discovery Exploratory Development Phase I Phase II Phase III Full Development Idea Years

5 Despite Significantly Increased Spending, R&D Productivity has Declined New drug approvals (NMEs) New drug approvals (NMEs) PhRMA member R&D spending Pharma Innovation gap 55 $ 50 $ 45 $ 40 $ 35 $ 30 $ 25 $ Pharma R&D ($ billion) $ 15 $ $ 5 $ 0 0 $ Source: Burril & Company, US Food and Drug Administration

6 Attrition Rates Have Increased at Each Stage of Development Pammolli F, Magazzini L, Riccaboni M. The productivity crisis in pharmaceutical R&D. Nat Rev Drug Discov Jun;10(6):

CNS Disease Burden: A Compelling Reason to

(# of years lost due to ill-health, disability

7 CNS Disease Burden: A Compelling Reason to Invest Central Nervous System (CNS) Diseases Cost Europe $1 Trillion per Year Burden of Disease: Disability-Adjusted Life Years (DALY) (# of years lost due to ill-health, disability or early death) Source: WHO, 2004 Source: Nature,

8 Challenges in CNS Drug Development Brain inviolate, biology unclear, genetics complex Few validated molecular targets Molecular targets for major pharmacological classes (antidepressants, anxiolytics, antipsychotics), decades old Until recently, we ve been looking under the same stones! Few compelling biomarkers Most animal models not true disease models Used to screen for known pharmacology Evaluate effects on behavioral dimensions (anxiety, apathy, anhedonia) that may not readily translate to relevant condition in humans

9 Is Nosology Constraining Innovation? Diagnostic system is phenomenological, based on observed or reported symptoms/complaints Classification is not biologically determined (though clinically useful) Co-morbidity more the rule than the exception Heterogeneity of patient populations confounds signal detection Since DSM informs regulatory pathway, development has been focused on currently defined syndromes

10 Signs of Change The National institute of Mental Health (NIMH) has not changed its position on DSM-5 It is increasingly evident that mental illness will be best understood as disorders of brain structure and function that implicate specific domains of cognition, emotion, and behavior. This is the focus of the NIMH s Research Domain Criteria (RDoC) project Insel/Lieberman News Release, APA, May 14, 2013

11 Breakthroughs in CNS Drug Development Require Rational Approaches Explication of human biology Deconstruction of complex behavioral syndromes Syndromes are complex phenotypes Syndromes are polygenic and multi-factorial Identification of endophenotypes to inform gene analysis, clarify genetic determinants, and identify relevant targets Development of more relevant animal models to facilitate translational efforts

12 In Conclusion: Have We Reached an Inflection Point? Neuroscience basic research knowledge exploding Preclinical biology, genetics Human experimental biology platforms being refined/incorporated into development paradigms Neuroimaging, biomarker development, quantitative neuropsych Clarification of functional domains/relevant neurocircuitry should allow for more effective derisking in earlier phases of development Above trends should positively influence Industry s investment posture

13 A Return to Rational CNS Drug Development Part 1: Translational and early Development Strategies and Tools Doug Feltner and Bill Potter Part 2: Designing the Right Series of Experiments Atul Mahableshwarkar and Gary Sachs Part 3: Operational Challenges Carla Canuso and Amir Kalali

Silver Linings Playbook: The Positive Side of Negative Trials ISCTM 13th Annual Scientific Meeting February 2017

Silver Linings Playbook: The Positive Side of Negative Trials ISCTM 13th Annual Scientific Meeting 21-23 February 2017 Steven J. Romano, MD Past President, ISCTM and EVP, Chief Science Officer, Mallinckrodt