NOVEL INDICATIONS: Experiences from a Study in MDD with Mixed Features (Mixed Depression)

Transcription

1 NOVEL INDICATIONS: Experiences from a Study in MDD with Mixed Features (Mixed Depression) 11 APRIL 2013 Josephine Cucchiaro, PhD Vice President Clinical Operations & Project Management Sunovion Pharmaceuticals

2 Disclosures I am a full time employee of Sunovion Pharmaceuticals

3 Overview 1. MDD with mixed features (mixed depression) 2. Lurasidone development programs have provided insight into potential new indications PEARL schizophrenia PREVAIL bipolar depression 3. RESOLVE Study in mixed depression Definition and characterization of the diagnosis Baseline characteristics of enrolled patients

4 WHAT IS MIXED DEPRESSION?

5 The majority of bipolar depressive episodes have symptoms of mania Number of DSM-IV Manic Symptoms During an Index Episode of Bipolar Depression in STEP-BD (N=1,380) Goldberg et al AJP 2009

6 Epidemiology of Mixed Depression Large-scale studies have confirmed high rates of concomitant subsyndromal hypomania among MDD population (~40-50%) (P. Zimmerman et al., Arch.Gen Psych. 2009; T. Suppes et al. Arch. Gen Psych 2005; J. Angst et al. AJP 2010; J. Goldberg et al., Am J Psych 2009, Benazzi et al., 2007, 2008; M. Frye et al., Am J Psych 2009; Benazzi and Akiskal, 2006) Prevalence of mixed depression (7-9%) approaches that observed for MDD alone (10%) (J. Angst et al. AJP 2010; P. Zimmerman et al., Arch.Gen Psych. 2009) Compared with MDD patients, mixed depression patients display higher rates of comorbidity with: Substance abuse disorders (P. Zimmerman et al., Arch.Gen Psych. 2009; Dodd et al., J Aff Dis 2010) Behavioral problems and criminal acts (P. Zimmerman et al., Arch.Gen Psych. 2009; Angst et al., 2010) Panic disorder (Zimmerman et al., 2009) Suicidality (Balazs et al., 2006; Angst et al., 2010; Goldberg et al., 1998; Judd and Akiskal, 2003) Overrepresented in women (Suppes et al., 2005, Akiskal and Benazzi, 2003) Associated with poorer long-term clinical outcomes compared with pure MDD (Dodd et al., 2010, Angst et al., 2010) 6

7 DSM-5: Major Depressive Episode With Mixed Features Full criteria for a major depressive episode and at least 3 of the following symptoms are present nearly every day during the episode: Elevated, expansive mood Inflated self-esteem or grandiosity Flight of ideas or subjective experience that thoughts are racing More talkative than usual or pressure to keep talking Increase in energy or goal-directed activity (either socially, at work or school, or sexually) Increased or excessive involvement in activities that have a high potential for painful consequences (eg, engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments) Decreased need for sleep (feeling rested despite sleeping less than usual [to be contrasted from insomnia]) Symptoms of mood elevation excluded from core defining symptoms: Irritability, psychomotor agitation, distractibility, insomnia 7

8 Translational evidence from late phase studies Can this be achieved? Considerations: Pharmacological profile Clinical data in schizophrenia and bipolar depression

9 Schizophrenia Program: Depressive Symptom Change - Pooled Data a PANSS Items Anxiety/Depression MADRS Mean Change from Baseline Anxiety * Depression N=135 N=181 N=135 N=181 * Mean Change from Baseline Placebo 80mg N=83 N=86 * Baseline: Anxiety Placebo 3.67, Lurasidone 3.83, Depression Placebo 2.90, Lurasidone 3.04 LOCF at end point *p<0.05 using ANCOVA a Studies 006, 196 ECNP 2005 Baseline: Placebo 14.5, Lurasidone 14.2 LOCF at end point *p<0.05 using ANCOVA a Study 196 ECNP 2005 Nakamura et al, (2009) J Clin Psych; Ogasa et al (2013) Psychopharmacology

10 PREVAIL Studies in Bipolar Depression MADRS: Primary Endpoint PREVAIL Monotherapy PREVAIL Adjunctive Therapy LS Mean Change from Baseline Baseline Placebo (n=162) ** * Week ** * Lurasidone mg (n=161) Effect size (MMRM): Lurasidone mg: 0.51 Lurasidone mg: 0.51 ** *** *** *** Lurasidone mg (n=162) Baseline mean *** *** LS Mean Change from Baseline Effect size (MMRM): Lurasidone + Li/VPA: 0.34 Placebo + Li/VPA Lurasidone + Li/VPA (n=161) (n=179) Baseline mean *P 0.05; **P 0.01; ***P Loebel A, et al., Am J Psych, in press

11 Post hoc analysis: MADRS Change for Subjects With and Without Subthreshold Hypomania PREVAIL Monotherapy Group 1: patients above or below the median Baseline YMRS score of 4 11

12 RESOLVE Study: Operational Criteria for Mixed Depression Diagnosis Full criteria for a Major Depressive Episode (at least 2 weeks in duration) AND 2-3 manic symptoms occurring nearly every day (present for at least the past 2 weeks) Manic symptoms to be consistent with DSM 5 list (non-specific symptoms of irritability, distractibility and psychomotor agitation are excluded) 12

13 Convincing management to fund a novel program Opinion of academic experts and the relevant literature on high unmet medical need for this population Stressed rationale for use of lurasidone as a potential treatment Advocated for the position that this study, while being high risk, would contribute to a better understanding of this population Study could provide insights for future product development programs

14 RESOLVE Study Design Double Blind Open Label Screening 3-14 days Baseline Day 0 Lurasidone mg/d Placebo Extension Study 6 weeks 6 months 14

15 Key Entry Criteria 18 to 75 years of age Diagnosed with an MDE (diagnosed by DSM-IV-TR, and confirmed by the modified SCID-CT) MADRS total score of 26 at both screening and baseline visits 2-3 manic symptoms to be consistent with DSM 5 list (non-specific symptoms of irritability, distractibility and psychomotor agitation are excluded) 15

16 DO INVESTIGATORS UNDERSTAND THE POPULATION UNDER STUDY?

17 Ensuring accurate diagnosis Thorough discussion of the diagnosis at Investigator s Meetings Measures to validate and confirm the diagnosis included in trial procedures Modified SCID-CT (to include assessment of mixed features)

18 Objections to the Diagnosis The proposed diagnosis does not exist or is very rare Patients with this clinical presentation are bipolar spectrum patients Recruitment will be very difficult

19 I understand the criteria for diagnosis of a major depressive episode with mixed features (subthreshold hypomanic symptoms) 3% 1) I have no understanding of this diagnosis 5% 35% 57% 2) I have limited understanding of this diagnosis 3) I have a moderate to good understanding of this diagnosis 4) I fully understand this diagnosis

20 1% How often do you see patients with an episode of major depressive disorder with mixed features (subthreshold hypomanic symptoms) in clinical practice? 11% 1) I rarely observe this condition (~2-3 cases/year) 48% 39% 2) I sometimes observe this condition (~1 case/month) 3) I often observe this condition (~1 case/week) 4) I never observe this condition

21 RESOLVE Study: Baseline Demographics Randomized Subjects (N=50) Male, n (%) 14 (28.0%) Age, years Mean (SD) 42.4 (14.7%) Age 30, n (%) 12 (24.0%) Age 31-50, n (%) 23 (46.0%) Age 51, n (%) 15 (30.0%) Race, n (%) Caucasian 29 (58.0%) Black 19 (38.0%) Other 2 (4.0%) Suppes et al. Presented ACNP 2012

22 RESOLVE Study: Baseline Clinical Characteristics Mean (SD) Number of Lifetime Major Depressive Episodes Total Number 6.1 (6.4) Number with Mixed Features 4.6 (5.9) Duration of Current Episode, months Major Depressive Features 4.6 (3.2) Concurrent Mixed Features 3.7 (3.3) MADRS Score 33.2 (4.8) CGI-S Score 4.6 (0.7) YMRS Score 12.7 (5.0) HAM-A Total Score 16.6 (6.9) Sheehan Disability Scale Total Score 19.1 (6.3) Suppes et al. Presented ACNP 2012

23 RESOLVE Study: Baseline Manic Symptoms Elevated, Expansive Mood Inflated Self-esteem, Grandiosity More Talkative or Pressure to Keep Talking Flight of Ideas or Racing Thoughts Increased Energy or Goal-Directed Activity Increased or Excessive Involvement in Risky Activities Decreased Need for Sleep Total Manic Symptoms = 2 Total Manic Symptoms = 3 Proportion Reporting Manic Symptoms, % (N=50) Suppes et al. Presented ACNP 2012

24 RESOLVE Study: Excluded Manic Symptoms Frequency of manic symptoms occurring on most days in the past 2 weeks that are not included in the study or DSM-5 criteria for mixed depression Proportion Reporting, % Suppes et al. Presented ACNP 2012

25 RESOLVE Study: Psychiatric Family History 100% Maternal 80% 72% Percentage 60% 40% 20% 0% 0% Schizophrenia 11% Bipolar Disorder 11% 6% 0% Depression Anxiety Alcoholism Substance Abuse 6% Other N=18 25

26 RESOLVE Study: Psychiatric Family History 100% Paternal 80% Percentage 60% 40% 37% 37% 20% 0% 11% Schizophrenia 5% Bipolar Disorder 0% 11% Depression Anxiety Alcoholism Substance Abuse 0% Other N=19 26

27 Conclusions Innovative drug development within established drug classes can be pursued Requires thorough understanding of the pharmacologic and clinical profile of the molecule Education and discussion with investigators and other key stakeholders is needed