Objectives PBA Introduction and Background PBA Burden of Illness - PDF document

Managing Your Emotional Health with MS: PBA Dr. Cherie Lovelace-Hyder Senior Medical Science Liaison Avanir Pharmaceuticals 1 Objectives • PBA Introduction and Background • PBA Burden of Illness • PBA Diagnosis • PBA Treatment – Nuedexta – MOA – STAR Trial – PRISM and PRISM II • Summary 2 1

PBA: Pseudobulbar Affect Characterized by involuntary, sudden and • frequent episodes of laughing and/ or crying Episodes are disproportionate to or • incongruent with the patient’s underlying emotional state PBA occurs secondary to a variety of otherwise • unrelated neurologic conditions NEUDEXTA [Package Insert]. Aliso Viej o, CA : Avanir Pharmaceuticals, Inc; 2011. 3 3 Terminology of PBA Various terms have been used interchangeably with PBA Emotional Incontinence Pathological Laughing and Crying Emotional Dyscontrol Pseudobulbar Emotionalism Affective Lability Affect Forced or Involuntary Crying Emotional Lability Pathological Emotionality Miller A. J Neurol S ci. 2006 Jun 15;245(1-2):153-9. 4 4 2

PBA: Prevalence in Neurologic Disorders Recent Literature Range of PBA Prevalence Estimates Estimates by Underlying Condition 1-22 70 ALS 4 49% Patients With PBA (%) 60 MS 11 10% 50 40 Stroke 22 11% 30 20 TBI 1 11% 10 0 Parkinson’s 21 5% ALS Dementia MS Parkinson’s Stroke TBI PBA prevalence estimates from scientific literature 1. Tateno A, et al. J Neuropsychiatry Clin Neurosci. 2004:16(4):426-434. 2. Caroscio JT, et al. Neurol Clin. 1987;5(1):1-8. 3. Miller RG, et al. Neurology. 1999;52(7):1311-1323. 4. Gallagher JP. Acta Neurol Scand. 1989;80(2):114-117. 5. Zimmerman EK, et al. Cogn Behav Neurol . 2007;20(2):79-82. 6. Ziegler LH. Arch Neurol Psychiatry. 1930;24(5):930-936. 7. Gubbay SS, et al. J Neurol . 1985;232(5):295- 300. 8. Pratt RT. J Neurol Neurosurg Psychiatry. 1951;14(4):326-335. 9. Starkstein SE, et al. J Neurol Neurosurg Psych . 1995;59:55-60. 10. Data on file. Avanir Pharmaceuticals, Inc; Aliso Viejo, CA; 2006. 11. Feinstein A, et al. Arch Neurol. 1997;54(9):1116-1121. 12. Langworthy OR, et al. Am J Psychiatry . 1941;98:243-249. 13. Cottrell SS, Wilson SAK. J Neurol Psychopathol. 1926;7:1-30. 14. Kim JS, Choi-Kwon S. Neurology. 2000;54(9):1805-1810. 15. Morris PL, et al. Aust N Z J Psychiatry. 1993;27(4):601-605. 16. Tang WK, et al. J Neurol. 2004;251(7):865-869. 17. House A, et al. BMJ. 1989;298(6679):991-994. 18. Robinson RG, et al. Am J Psychiatry. 1993;150(2):286-293. 19. Zeilig G, et al. Brain Inj. 1996;10(8):591-597. 20. Strowd RE, et al. J Neurol. 2010;257(8):1382-1387. 21. Siddiqui MS, et al. World J Biol Psychiatry. 2009;10(3):234-240. 22. Tang WK, et al. J Neurol Neurosurg Psychiatry 2009;80:1082–1086. 5 Pseudobulbar affect (PBA)- Etiology 1,2 Disruption of the Neural Network Controlling Emotional Motor Expression • Believed to result from – Loss of frontal voluntary control or- – Detachment from appropriate adjustments to social/cognitive context due to lesions in the cortico-ponto-cerebellar pathways 1. Wilson SAK. J Neurol Psychopathol . 1924;4(16):299-333. 2. Parvizi J, et al. J Neuropsychiatry Clin Neurosci . 2009;21(1):75-87. 6 3

Reported Causes of Pseudobulbar Affect Caused by event- Caused by Disease- • Stroke • ALS • Traumatic brain injury • Multiple sclerosis • Brain tumors • Alzheimer’s disease • Brainstem AVM / aneurysm • Parkinson’s disease • Hypoxic brain injury • CNS lipid storage diseases • Corticobasal degeneration • Frontotemporal dementia • Herpes encephalitis • Neurosyphilis • Normal pressure hydrocephalus • Primary lateral sclerosis • Progressive supranuclear palsy • Wilson’s disease Wortzel HS, et al. CNS Drugs . 2008;22(7):531-545. 7 Schiffer R, Pope LE. J Neuropsychiatry Clin Neurosci . 2005; 17(4): 447-454. Proposed Diagnostic Criteria for PBA • Episodes of involuntary or exaggerated emotional expression (crying, laughing, etc) Episodes represent change from person’s usual emotional reactivity – Episodes may be incongruent or in excess of the person’s mood – – Episodes are independent or in excess of any provoking stimulus The disturbance causes clinically significant distress or impairment • in social or occupational functioning S ymptoms are not accounted for by another neurological or • psychiatric disorder S ymptoms are not the direct physiological effect of a substance • Cummings JL, et al. CNS S pect r . 2006 Jun;11(6):1-7. 8 8 4

Clinical Presentation of Pseudobulbar affect (PBA)- • Involuntary and uncontrollable outbursts of crying, laughing or other emotional displays • Episodes are: – Paroxysmal (sudden and intense) – Relatively brief (seconds to minutes) – Frequent – Stereotypical (frequency, duration, intensity) • Emotional expressions may be exaggerated or unassociated with underlying mood 1. Schiffer R, Pope LE. J Neuropsychiatry Clin Neurosci . 2005;17(4):447-454. 2. Wortzel HS, et al. CNS Drugs . 2008;22(7):531-545. 3. Wilson SAK. J Neurol Psychopathol . 1924;4(16):299-333. 9 Who Treats Pseudobulbar Affect? • Approximately 15,000 physicians manage the majority of PBA patients – Neurologists – Psychiatrists – Long Term Care Medical Directors – Physiatrists (neuro-rehab) – Geriatricians 10 10 5

Clinical Observation: The Burden of PBA • Clinicians and researchers have consistently observed for over a century that PBA may cause: – Distress to both patients and caregivers 1-3 – Impaired social and occupational function 4-6 – Embarrassment, social phobia, withdrawal, and isolation 4,7 – Feelings of frustration and humiliation 2,8 – Inability to participate in rehabilitative therapy 9 1. Oppenheim H. Textbook of Nervous Diseases for Physicians and Students . 5th ed. Edinburgh, United Kingdom: Otto Schulze & Company; 1911. 2. Wilson SAK. J Neurol Psychopathol . 1924;4(16):299-333. 3. Miller A. J Neurol Sci . 2006;245(1-2):153-159. 4. Dark FL, et al. Aust N Z J Psychiatry . 1996;30(4):472-479. 5. Arciniegas DB, Topkoff J. Semin Clin Neuropsychiatry . 2000;5(4):290-306. 6. Shaibani AT, et al. Neuropsychiatry Neuropsychol Behav Neurol . 1994;7(4):243-250. 7. Robinson RG, et al. Am J Psychiatry . 1993;150(2):286-293. 8. Schiffer R, Pope LE. J Neuropsychiatry Clin Neurosci . 2005;17(4):447-454. 9. Wortzel HS, et al. CNS Drugs . 2008;22(7):531-545. 11 Quality of Life and Quality of Relationships Effect of PBA • Uncontrollable laughter, 50 PBA Controls tearfulness, and anger negatively affected the QOL for 40 * * PBA patients Visual Analog Scale 30 • Personal relationships of patients with PBA were 20 significantly more negatively affected than neurologic 10 controls 0 QOL QOR * P < .05 vs. controls Q: To what degree has uncontrollable laughter, tearfulness, or anger has affected the quality of life/relationships in the past week? (0=Not at all; 100=continuously) 1 Avanir Data on File, 2006. Quality of Life = QOL. Quality of Relationships = QOR. 12 12 6

Unmet Need in the Treatment of PBA • Patients would benefit from a safe and effective treatment option • American Academy of Neurology guidelines – 2003: PBA included as one of the leading symptoms of ALS for physicians to recognize and manage – 2009: Practice Parameter Update recommended: “For treatment of pseudobulbar affect, dextromethorphan and quinidine should be considered if approved by the US Food and Drug Administration.” 1 1. Miller RG, et al. Neurology . 2009;73(15):1218-1226. 13 THERAPEUTIC RATIONALE AND EFFICACY 14 7

NUEDEXTA Mechanism of Action: Modulation of Glutamate Presynaptic inhibition 1 of glutamate release Postsynaptic glutamate 2 response modulation  NUEDEXTA acts on sigma-1 receptors and NMDA receptors in the brain  The exact mechanism of action by which NUEDEXTA exerts therapeutic effects in patients with PBA is unknown. 15 15 15 Sigma Receptor Binding Sites in the Brain The shaded areas represent the approximate densities of binding sites. The densities of binding sites are inferred from data in animal tissue, and may not be homogenous in individual areas. The highest density of binding sites was found in the cranial nerve nuclei with an average of 453 fmol/mg. Gundlach AL, et al. J Neurosci. 1986 Jun;6(6):1757-70. 16 16 8

PBA Etiology: Current Model Cerebro-Ponto-Cerebellar Circuit 1-4 Normal  Under normal conditions, cerebro-ponto-cerebellar circuitry is intact and works in concert to coordinate appropriate emotional expression Voluntary laughing/crying 1. Parvizi J, et al. Brain . 2001;124(Pt 9):1708-1719. 2. Haiman G, et al. J Neurol S ci . 2008;271(1-2):137-147. 3. Miller A, et al. Expert Rev Neurot her . 2011;11(7):1077-1088. 4. Parvizi J, et al. J Neuropsychiat ry Clin Neurosci . 2009;21(1):75-87. 17 17 PBA Etiology: Current Model Cerebro-Ponto-Cerebellar Circuit 1-3 PBA  Lesions within the cerebro-ponto-cerebellar circuitry may disrupt the ability of the cerebellum to receive critical information and “ fine- tune” an appropriate emotional expression Involuntary laughing/crying 1. Parvizi J, et al. Brain . 2001;124(Pt 9):1708-1719. 2. Miller A, et al. Expert Rev Neurot her . 2011;11(7):1077-1088. 3. Parvizi J, et al. J Neuropsychiat ry Clin Neurosci . 2009;21(1):75-87. 18 18 9