Cognitive Impairment in Major Depressive Disorder as a Target for Drug Development

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1 Cognitive Impairment in Major Depressive Disorder as a Target for Drug Development Maurizio Fava, MD Director Clinical Research Program Executive Vice Chair Department of Psychiatry Executive Director Clinical Trials Network and Institute (CTNI) Massachusetts General Hospital Slater Family Professor of Psychiatry Harvard Medical School

2 Type Advisory Board/ Consultant Disclosures (lifetime): Maurizio Fava, MD Company Abbott Laboratories; Affectis Pharmaceuticals AG; Alkermes, Inc.; Amarin Pharma Inc.; Aspect Medical Systems; AstraZeneca; Auspex Pharmaceuticals; Avanir Pharmaceuticals; AXSOME Therapeutics; Bayer AG; Best Practice Project Management, Inc.; BioMarin Pharmaceuticals, Inc.; Biovail Corporation; BrainCells Inc; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon, Inc.; Cerecor; CNS Response, Inc.; Compellis Pharmaceuticals; Cypress Pharmaceutical, Inc.; DiagnoSearch Life Sciences (P) Ltd.; Dinippon Sumitomo Pharma Co. Inc.; Dov Pharmaceuticals, Inc.; Edgemont Pharmaceuticals, Inc.; Eisai Inc.; Eli Lilly and Company; EnVivo Pharmaceuticals, Inc.; epharmasolutions; EPIX Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Fabre-Kramer Pharmaceuticals, Inc.; Forest Pharmaceuticals, Inc.; Forum Pharmaceuticals; GenOmind, LLC; GlaxoSmithKline; Grunenthal GmbH; i3 Innovus/Ingenis; Janssen Pharmaceutica; Jazz Pharmaceuticals, Inc.; Johnson & Johnson Pharmaceutical Research & Development, LLC; Knoll Pharmaceuticals Corp.; Labopharm Inc.; Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante, Inc.; Merck & Co., Inc.; MSI Methylation Sciences, Inc.; Naurex, Inc.; Nestle Health Sciences; Neuralstem, Inc.; Neuronetics, Inc.; NextWave Pharmaceuticals; Novartis AG;Nutrition 21; Orexigen Therapeutics, Inc.; Organon Pharmaceuticals; Otsuka Pharmaceuticals; Pamlab, LLC.; Pfizer Inc.; PharmaStar; Pharmavite LLC.; PharmoRx Therapeutics; Precision Human Biolaboratory; Prexa Pharmaceuticals, Inc.; PPD; Puretech Ventures; PsychoGenics; Psylin Neurosciences, Inc.; RCT Logic, LLC ( formerly Clinical Trials Solutions, LLC); Rexahn Pharmaceuticals, Inc.; Ridge Diagnostics, Inc.; Roche; Sanofi- Aventis US LLC.; Sepracor Inc.; Servier Laboratories; Schering-Plough Corporation; Solvay Pharmaceuticals, Inc.; Somaxon Pharmaceuticals, Inc.; Somerset Pharmaceuticals, Inc.; Sunovion Pharmaceuticals; Supernus Pharmaceuticals, Inc.; Synthelabo; Takeda Pharmaceutical Company Limited; Tal Medical, Inc.; Tetragenex Pharmaceuticals, Inc.; TransForm Pharmaceuticals, Inc.; Transcept Pharmaceuticals, Inc.; Vanda Pharmaceuticals, Inc. Speaking/ Publishing Research Support Stock/Other Financial Options Adamed, Co; Advanced Meeting Partners; American Psychiatric Association; American Society of Clinical Psychopharmacology; AstraZeneca; Belvoir Media Group; Boehringer Ingelheim GmbH; Bristol-Myers Squibb; Cephalon, Inc.; CME Institute/Physicians Postgraduate Press, Inc.; Eli Lilly and Company; Forest Pharmaceuticals, Inc.; GlaxoSmithKline; Imedex, LLC; MGH Psychiatry Academy/Primedia; MGH Psychiatry Academy/Reed Elsevier; Novartis AG; Organon Pharmaceuticals; Pfizer Inc.; PharmaStar; United BioSource,Corp.; Wyeth-Ayerst Laboratories. Abbot Laboratories; Alkermes, Inc.; American Cyanamid;Aspect Medical Systems; AstraZeneca; Avanir Pharmaceuticals; BioResearch; BrainCells Inc.; Bristol-Myers Squibb; CeNeRx BioPharma; Cephalon; Clintara, LLC; Covance; Covidien; Eli Lilly and Company;EnVivo Pharmaceuticals, Inc.; Euthymics Bioscience, Inc.; Forest Pharmaceuticals, Inc.; Ganeden Biotech, Inc.; GlaxoSmithKline; Harvard Clinical Research Institute; Hoffman-LaRoche; Icon Clinical Research; i3 Innovus/Ingenix; Janssen R&D, LLC; Jed Foundation; Johnson & Johnson Pharmaceutical Research & Development; Lichtwer Pharma GmbH; Lorex Pharmaceuticals; Lundbeck Inc.; MedAvante; Methylation Sciences Inc; National Alliance for Research on Schizophrenia & Depression (NARSAD); National Center for Complementary and Alternative Medicine (NCCAM); National Institute of Drug Abuse (NIDA); National Institute of Mental Health (NIMH); Neuralstem, Inc.; Novartis AG; Organon Pharmaceuticals; PamLab, LLC.; Pfizer Inc.; Pharmacia-Upjohn; Pharmaceutical Research Associates., Inc.; Pharmavite LLC;PharmoRx Therapeutics; Photothera; Reckitt Benckiser; Roche Pharmaceuticals; RCT Logic, LLC (formerly Clinical Trials Solutions, LLC); Sanofi-Aventis US LLC; Shire; Solvay Pharmaceuticals, Inc.; Stanley Medical Research Institute (SMRI); Synthelabo; Wyeth-Ayerst Laboratories Equity Holdings: Compellis; PsyBrain, Inc. Royalty/patent, other income: Patents for Sequential Parallel Comparison Design (SPCD), licensed by MGH to Pharmaceutical Product Development, LLC (PPD); and patent application for a combination of Ketamine plus Scopolamine in Major Depressive Disorder (MDD), licensed by MGH to Biohaven. Copyright for the MGH Cognitive & Physical Functioning Questionnaire (CPFQ), Sexual Functioning Inventory (SFI), Antidepressant Treatment Response Questionnaire (ATRQ), Discontinuation-Emergent Signs & Symptoms (DESS), Symptoms of Depression Questionnaire (SDQ), and SAFER; Lippincott, Williams & Wilkins; Wolkers Kluwer; World Scientific Publishing Co. Pte.Ltd.

3 How do we Assess and Define Cognitive Impairment in MDD? How Common is It? What is its Impact on MDD? Is Cognitive Impairment in MDD a Reasonable Target for Drug Development?

4 Objective vs Subjective Measures of Cognition Plus - These are Objective Measures, Relatively Devoid of Biases Performance on Standardized Cognitive Tests Minus - The Norms are Population-Based and Do Not Reflect Premorbid Performance Levels Self-Reported Levels of Functioning Plus Some of These Measures Capture the Perception of Change From Premorbid Levels Self-Reported Perception of One s Cognitive and Executive Function Minus Depression and/or Anxiety May Affect the Perception of Cognitive Function

5 bjective Measures of Cognitive Impairment (CI) in Depression Austin et al, Journal of Affective Disorders, 1992; 25, 21 29

6 Meta-Analysis of Studies Using Objective Measures of Cognitive Impairment (CI) in Depression Major Depressive Disorder Is Associated With Broad Impairments on Neuropsychological Measures of Executive Function: A Meta-Analysis and Review. Snyder, Hannah Psychological Bulletin. 139(1):81-132, January DOI: /a Figure 1 Weighted mean effect sizes for all analyses. Error bars are 95% confidence intervals. Compared to healthy control participants, patients with major depressive disorder are significantly impaired on all tasks. Executive function (EF) composite measures are indicated with diamond symbols, and individual measures within each EF component by circle symbols in the same color. Pink circles indicate non-ef comparison measures. The solid gray vertical line indicates the psychomotor speed composite score effect size: Measures for which the lower error bar (95% confidence interval) does not pass the dashed line are significantly greater than 0, and those that do not pass the solid gray line have significantly larger effect sizes than the psychomotor speed effect size. Comp. = composite score; WCST = Wisconsin Card Sorting Test; TMT-B = Trail Making Test Part B; TMT-A = Trail Making Test Part A; ID/ED = Intradimensional/Extradimensional; WM = working memory; DMTS = delayed-match-to-sample; VF = verbal fluency.

7 Cognition Subscale of the CPFQ Fava et al, Reliability and Validity of the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire. Psychother Psychosom 2009;78:91 97

8 Prevalence of Subjectively-Defined Cognitive Impairment in MDD TAK316 Subjective impairment CPFQ (<moderately) NO CPFQ (>markedly) YES 267 (58%) 195 (42%) Fava et al, in preparation; this is a baseline, post-hoc analysis

9 Differences in Depression Severity and Functioning in MDD with and without Cognitive Impairment Subjectively CPFQ (<moderately impaired) n=267 (58%) CPFQ (>markedly impaired) n=195 (42%) TAK316 MADRS 31.5 ± ± 4.3 SDS 18.2 ± 5.3 (n=169) 20.9 ± 6.2 (n=134) Fava et al, in preparation; this is a baseline, post-hoc analysis

10 How does Cognitive Impairment in Depression Relate to the Heterogeneity of MDD and its Various Symptoms?

11 Do the Subtypes of MDD Affect Cognition Differently? Major Depressive Disorder With Atypical Features Major Depressive Disorders With Melancholic Features Major Depressive Disorder with Anxious Distress Cognitive Impairment Major Depressive Disorder With Irritability and Anger Attacks Major Depressive Disorder With Psychotic Features

12 Relationship Between Depressive and Cognitive Symptoms in MDD

13 What is the Overlap Between Subjective and Objective Cognitive Impairment in MDD?

14 Distribution of MDD patients with Cognitive Impairment Subjective Self-reported Cognitive Impairment in MDD patients scoring at least markedly impaired (>5) on at least 2 of the 4 cognitive items in CPFQ markedly impaired (+ Subj) moderately impaired (- Subj) Objective Cognitive Impairment in MDD patients scoring >1 SD below norm on 2 or more of DSST, TMT-B, CRT, One-back 1SD impaired in 2 test (+ Obj) 1SD impaired in > 2 test (- Obj) 53% (n=318) (n=283) 47% 43% (n=259) (n=343) 57% Subjective AND/OR Objective Cognitive Impairment in MDD + Subj and + Obj - Subj and + Obj 24% (n=144) 28% (n=168) + Subj and - Obj - Subj and - Obj 19% (n=174) 29% (n=115) Fava et al, in preparation; this is a baseline, post-hoc analysis CONNECT

15 Differences in Depression Severity and Functioning in MDD with and without Cognitive Impairment CONNECT Subjectively CPFQ (<moderately impaired) n=318 (53%) CPFQ (>markedly impaired) n=283 (47%) Objectively Not/Less impaired (<1SD) n=259 (43%) Impaired (>1SD) n=343 (57%)* MADRS 30.9 ± ± 4.0 MADRS 31.6 ± ± 3.8 PDQ 37.4 ± ± 9.1 PDQ 42.2 ± ± 11.6 UPSA 78.5 ± ± 12.9 UPSA 80.6 ± ± 13.9 *patients scoring >1 SD below norm on 2 or more of DSST, TMT- B, CRT, One-back (Objectively impaired) Fava et al, in preparation; this is a baseline, post-hoc analysis

16 Do Antidepressant Therapies Adequately Address Cognitive Impairment in MDD?

17 Changes in Neuropsychological Testing After Antidepressant Therapy in MDD Chang et al, Brain, Behavior, and Immunity 26 (2012) 90 95

18 Subjective Cognitive Improvement in MDD Remitters and non-remitters Baer et al, ANNALS OF CLINICAL PSYCHIATRY 2014;26(4):

19 Proportion of MDD Subjects with Residual Physical and Cognitive Deficits Based on CPFQ Scores (N=117) Fava M et al, J Clin Psych 2006; 67:

20 Percentages of Impairment in CPFQ Domains Among MDD Responders to SSRI Treatment (n=93) 60.00% 50.00% 40.00% 30.00% 20.00% 10.00% Any Impairment Minimal sxs Moderate sxs 0.00% Freeman et al, in preparation

21 Percentages of AE-Related Residual Impairment in CPFQ Domains Among MDD Responders to SSRI Treatment 18% 16% 14% 12% 10% 8% 6% 4% 2% 0% Adv Event % Adv Event % Freeman et al, in preparation

Prediction of Work Skills b) Prediction of Community and

22 Depression and Cognitive Deficits are Independently Related to Functional Deficits in Mood Disorders a) Prediction of Work Skills b) Prediction of Community and Household Activities Bowie et al, Am J Psychiatry Sep;167(9):

Mean change from baseline in DSST correct number of symbols The Effects on Cognition Cannot Solely be Explained by the Improvement in Depressive Symptoms

Vortioxetine Direct effect VOR 10 VOR 20 DSST 66% 56% MADRS DSST VOR 10 VOR 20 DSST 34% 44% Indirect effect Vortioxetine significantly improves cognitive

23 Mean change from baseline in DSST correct number of symbols The Effects on Cognition Cannot Solely be Explained by the Improvement in Depressive Symptoms FOCUS Path-analysis shows that up to two thirds of the effect on cognition can be considered as independent effect, not mediated by improvement on mood Vortioxetine Direct effect VOR 10 VOR 20 DSST 66% 56% MADRS DSST VOR 10 VOR 20 DSST 34% 44% Indirect effect Vortioxetine significantly improves cognitive performance even after correcting for effect on mood Change from Baseline to Placebo (FAS, LOCF) Effect on DSST after correcting for effect on MADRS VOR 10mg VOR 20mg 2.59** 2.23** 14 Non-remitters MADRS>10 Non-responders MADRS<50% 12 Vortioxetine significantly improves cognitive function in both non-remitters and non-responders *** *** * ** 4 McIntyre et al. Int J Neuropsychopharmacol 30 April 2014:1-11. Epub ahead of print Pbo VOR 10mg VOR 20mg

24 Relationship between Changes in Functioning (SDS) and Cognition (CPFQ) in MDD Patients with Residual Apathy Correlation between SDS and CPFQ change in total score from baseline to endpoint in patients with MDD and residual apathy Rothschild et al, Comprehensive Psychiatry 55 (2014) 1 10; Baer et al, ANNALS OF CLINICAL PSYCHIATRY 2014;26(4):

25 Conclusions 40% to 55% of adults with MDD present with either subjective or objectively defined cognitive impairment The presence of cognition impairment in MDD is associated with greater illness severity and poorer functioning than MDD alone There is a poor correlation between core MDD symptoms and symptoms of cognitive impairment

26 Conclusions (cont.) Even among responders/remitters with MDD, residual cognitive impairment is common (30% to 40%) These residual symptoms are typically not due to the antidepressant therapy Changes in levels of functioning among MDD patients with residual symptoms are significantly accounted for by changes in cognitive symptoms

Novel Approaches to Address Treatment Resistant Depression: Targeting Multiple Mechanisms of Action

AXS-05 R&D Day April 24, 2018 Novel Approaches to Address Treatment Resistant Depression: Targeting Multiple Mechanisms of Action Maurizio Fava, MD Director, Division of Clinical Research, Massachusetts