managing your emotional health in ms - pba slides … · managing your emotional health with ms:...

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Managing Your Emotional Health with MS: PBA

Dr. Cherie Lovelace-HyderSenior Medical Science Liaison

Avanir Pharmaceuticals

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Objectives

• PBA Introduction and Background

• PBA Burden of Illness

• PBA Diagnosis

• PBA Treatment – Nuedexta

– MOA

– STAR Trial

– PRISM and PRISM II

• Summary

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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

3NEUDEXTA [Package Insert]. Aliso Viejo, CA : Avanir Pharmaceuticals, Inc; 2011.

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Terminology of PBA

Various terms have been used interchangeably with PBA

Miller A. J Neurol Sci. 2006 Jun 15;245(1-2):153-9.

Pseudobulbar Affect

Pathological Laughing and Crying

Emotional Lability

Affective Lability

Pathological Emotionality

Forced or Involuntary Crying

Emotional DyscontrolEmotionalism

Emotional Incontinence

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Range of PBA Prevalence Estimates by Underlying Condition1-22

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.

PBA: Prevalence in Neurologic Disorders

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60

50

40

30

20

10

0

TBI

Pat

ient

s W

ith P

BA

(%

)

StrokeParkinson’sMSALS Dementia

PBA prevalence estimates from scientific literature

ALS4 49%

MS11 10%

Stroke22 11%

TBI1 11%

Parkinson’s21 5%

Recent LiteratureEstimates

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Pseudobulbar affect (PBA)- Etiology1,2

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-cerebellarpathways

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.

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Caused by event-

• Stroke

• Traumatic brain injury

• Brain tumors

• Brainstem AVM / aneurysm

• Hypoxic brain injury

Caused by Disease-

• ALS

• Multiple sclerosis

• Alzheimer’s disease

• Parkinson’s disease

• CNS lipid storage diseases

• Corticobasal degeneration

• Frontotemporal dementia

• Herpes encephalitis

• Neurosyphilis

• Normal pressure hydrocephalus

• Primary lateral sclerosis

• Progressive supranuclear palsy

• Wilson’s disease

Reported Causes of Pseudobulbar Affect

Wortzel HS, et al. CNS Drugs. 2008;22(7):531-545. Schiffer R, Pope LE. J Neuropsychiatry Clin Neurosci. 2005; 17(4): 447-454.

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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

• Symptoms are not accounted for by another neurological or psychiatric disorder

• Symptoms are not the direct physiological effect of a substance

8Cummings JL, et al. CNS Spectr. 2006 Jun;11(6):1-7.

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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.

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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

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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 caregivers1-3

– Impaired social and occupational function4-6

– Embarrassment, social phobia, withdrawal, and isolation4,7

– Feelings of frustration and humiliation2,8

– Inability to participate in rehabilitative therapy9

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.

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Quality of Life and Quality of Relationships

• Uncontrollable laughter,

tearfulness, and anger

negatively affected the QOL for

PBA patients

• Personal relationships of

patients with PBA were

significantly more negatively

affected than neurologic

controls0

10

20

30

40

50

QOL QOR

Vis

ual A

nalo

g S

cale

PBA Controls

* *

*P < .05 vs. controls

Effect of PBA

1 Avanir Data on File, 2006. Quality of Life = QOL. Quality of Relationships = QOR.

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)

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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.

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THERAPEUTIC RATIONALE AND EFFICACY

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NUEDEXTA Mechanism of Action: Modulation of Glutamate

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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.

1 Presynaptic inhibition of glutamate release

2 Postsynaptic glutamate response modulation

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Sigma Receptor Binding Sites in the Brain

16Gundlach AL, et al. J Neurosci. 1986 Jun;6(6):1757-70.

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.

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PBA Etiology: Current Model

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Cerebro-Ponto-Cerebellar Circuit1-4

Normal

Under normal conditions, cerebro-ponto-cerebellar circuitry is intact and works in concert to coordinate appropriate emotional expression

1. Parvizi J, et al. Brain. 2001;124(Pt 9):1708-1719. 2. Haiman G, et al. J Neurol Sci. 2008;271(1-2):137-147. 3. Miller A, et al. Expert Rev Neurother. 2011;11(7):1077-1088. 4. Parvizi J, et al. J Neuropsychiatry Clin Neurosci. 2009;21(1):75-87.

Voluntarylaughing/crying

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PBA Etiology: Current Model

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Cerebro-Ponto-Cerebellar Circuit1-3

1. Parvizi J, et al. Brain. 2001;124(Pt 9):1708-1719. 2. Miller A, et al. Expert Rev Neurother. 2011;11(7):1077-1088. 3. Parvizi J, et al. J Neuropsychiatry Clin Neurosci. 2009;21(1):75-87.

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

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Why Combine Dextromethorphan and Quinidine?

1. NUEDEXTA™ (dextromethorphan hydrobromide and quinidine sulfate) capsules [prescribing information]. Aliso Viejo, CA: Avanir Pharmaceuticals, Inc; 2010. 2. ChemSpider. Accessed Jan 28, 2011.

Metabolized by CYP2D6

Dextrorphan

DM is rapidly metabolized by CYP2D6.

Dextromethorphan

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Increased DM Plasma Levels

1. NUEDEXTA™ (dextromethorphan hydrobromide and quinidine sulfate) capsules [prescribing information]. Aliso Viejo, CA: Avanir Pharmaceuticals, Inc; 2010. 2. ChemSpider. Accessed Jan 28, 2011.

Metabolized by CYP2D6

Dextrorphan

DM is rapidly metabolized by CYP2D6.

Dextromethorphan

1. Pope LE, et al. J Clin Pharmacol. 2004;44(10):1132-1142.2. Data on file: STAR Trial. Avanir Pharmaceuticals, Inc, Aliso Viejo, CA; 2009.

Q blocks

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CLINICAL EFFICACY

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Study DesignStudy 07-AVR-123

STAR Trial

• PBA populations

– ALS (n=197)

– MS (n=129)

Randomized n=107

N=326

n=110

n=109

Double-Blind Phase12 weeks

Extension Phase 12 weeks

NUEDEXTA 20/10 q12°

Placebo q12°

AVP 30/10 q12°

Pioro EP, et al. Ann Neurol. 2010;68(5):693-702.

NOTE: Only the NUEDEXTA 20/10 dosage form is FDA approved.

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Efficacy Endpoints

• Primary efficacy endpoint– Laughing/crying episode counts from patient diary

– Primary analysis is additional reduction in episode rates over placebo

• Additional Outcomes– CNS-LS score

– Neuropsychiatric Inventory (NPI)

– SF-36 Health Survey (SF-36)

– Beck Depression Inventory (BDI-II)

– Pain Rating Scale (PRS) score in patients with MS only

Data on file: STAR Trial. Avanir Pharmaceuticals, Aliso Viejo, CA; 2009.

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Reduction of PBA Episodes From BaselineStudy 07-AVR-123: Primary Endpoint

Reduction in Episode Rate over Placebo

Treatment EffectRelative to Placebo

*P<0.0001

*Longitudinal negative binomial regression with adjustment for baseline rate, diagnosis, and study siteAdapted from Pioro EP, et al. Ann Neurol. 2010;68(5):693-702.

* *

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PBA Weekly Episode Rate Reduction

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

00 1 2 3 4 5 6 7 8 9 10 11 12

Mea

n %

Ch

ang

e F

rom

Bas

elin

e

Study Week

20/10

Placebo*

* **

* * * * ** * *

NUEDEXTA

*P < .05 vs placeboData on file: STAR Trial. Avanir Pharmaceuticals, Aliso Viejo, CA; 2009.

The need for continued treatment should be reassessed periodically, as spontaneous improvement of PBA symptoms occurs in some patients.

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Remission No Episodes in Last 14 Study Days

*

Patients, %

Patients With “Remission”(EOS)

*P < .01 vs placeboAdapted from Pioro EP, et al. Ann Neurol. 2010;68(5):693-702.

NUEDEXTA

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Improvements in CNS-LSa ScoreStudy 07-AVR-123: Secondary Endpoint

-10

-8

-6

-4

-3

-1

0

-7

-2

-9

-5

CNS-LSScore at

EOS

14.3

12.8**

Baseline(Visit 1)

Day 15(Visit 2)

Day 29(Visit 3)

Day 57(Visit 4)

Day 84(Visit 5)

Placebo (BL=19.9) NUEDEXTA (BL=21.0)

LS Mean Change From

Baseline CNS-LS Score

*P < .05 vs placeboaThe Center for Neurologic Study-Lability Scale (CNS-LS) is a clinical trial scale used to assess PBA frequency and severity, validated in patients with ALS and MS. Data on file: STAR Trial. Avanir Pharmaceuticals, Aliso Viejo, CA; 2009.

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SAFETY AND TOLERABILITY

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Most Frequent Adverse Events (≥3% of Patients and ≥2X Placebo)

Study 07-AVR-123: Overall Safety Population

The most commonly reported adverse reactions leading to discontinuation were muscle spasticity (3%), respiratory failure (1%), abdominal pain (2%), asthenia (2%), dizziness (2%), fall (1%), and muscle spasms (2%).

AE Preferred Term, (%)NUEDEXTA

n=107Placebon=109

Diarrhea 13% 6%

Dizziness 10% 5%

Cough 5% 2%

Vomiting 5% 1%

Asthenia 5% 2%

Peripheral edema 5% 1%

Urinary tract infection 4% 1%

Influenza 4% 1%

Increased GGT 3% 0%

Flatulence 3% 1%

NUEDEXTA™ (dextromethorphan hydrobromide and quinidine sulfate) capsules [prescribing information]. Aliso Viejo, CA:Avanir Pharmaceuticals, Inc; 2010.

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A Consistent Safety Profile Across Trials

• In 4 phase 3 studies (controlled and open-label), 946 patients received at least 1 dose of dextromethorphan/quinidine in various strengths– 393 patients were exposed for at least 180 days, and 294 patients were

exposed for at least 1 year (median = 168 days)

• In addition to ALS and MS patients, open-label studies also enrolled 136 patients with PBA secondary to a wide variety of other underlying neurological conditions– Including stroke (n = 45) and traumatic brain injury (n = 23)

– Patients with underlying neurological diseases other than ALS and MS may experience adverse reactions other than those seen in the controlled trials

NUEDEXTA™ (dextromethorphan hydrobromide and quinidine sulfate) capsules [prescribing information]. Aliso Viejo, CA: Avanir Pharmaceuticals, Inc; 2010.

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NUEDEXTAIndication and Usage

• NUEDEXTA is indicated for the treatment of PBA

– PBA occurs secondary to a variety of otherwise unrelated neurological conditions and is characterized by involuntary, sudden, and frequent episodes of laughing and/or crying

– PBA episodes typically occur out of proportion or incongruent to the underlying emotional state


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NUEDEXTAUse in Special Populations

• Pregnancy: No adequate and well-controlled studies in pregnant women

• Nursing mothers: Not known whether NUEDEXTA is excreted in human milk

• Pediatric use: Safety and effectiveness have not been established

• Geriatric use:

– Similar pharmacokinetics in adult and geriatric patients

– No dosage adjustment or special monitoring required for geriatric patients

– Clinical studies of NUEDEXTA did not include sufficient numbers of patients aged

≥65 years to determine whether they respond differently than younger patients

• Renal and Hepatic impairment:

– Dose adjustment not required in patients with mild-to-moderate renal or hepatic impairment

– Severe patients not evaluated (increased drug levels likely)

NUEDEXTA™ (dextromethorphan hydrobromide and quinidine sulfate) capsules [prescribing information]. Aliso Viejo, CA:Avanir Pharmaceuticals, Inc; 2010.

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NUEDEXTA: Contraindicated in Patients…

• Concomitantly taking quinidine or related drugs

• With known hypersensitivity to NUEDEXTA or its components

• Concomitantly taking monoamine oxidase inhibitors (within 14 days)

• With certain risk factors for arrhythmia

– Prolonged QT interval

– Congenital long QT syndrome

– History of torsades de pointes

– Heart failure

– Atrioventricular block without an implanted pacemaker

• Concomitantly taking drugs that both prolong QT interval and are metabolized by CYP2D6 (eg, thioridazine and pimozide)


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NUEDEXTA Dosing

• One capsule daily by mouth for initial 7 days of therapy

• Beginning day 8, one capsule every 12 hours

• Patients should take NUEDEXTA exactly as prescribed:– No more than 2 capsules in a 24-hour period

– Make sure that there is an approximate 12-hour interval between doses

– Do not take a double dose after a dose is missed

• Need for continued treatment should be reassessed periodically, as spontaneous improvement may occur in some patients


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PRISM: A Novel Research Tool to Determine Prevalence of Pseudobulbar Affect

• Objective: To estimate PBA prevalence and impact on QoL across disease states commonly associated with PBA, utilizing a registry

• Methods:– Recruitment goal: PRISM intends to recruit ~500 sites nationwide; in turn,

the sites will enroll a total of 10,000 patients at risk for PBA due to underlying MS, AD, ALS, PD, stroke, or TBI

– Recruitment procedure: Sites enroll in PRISM via a centralized Web portal1

and register with a central IRB; upon IRB approval, each activated site began screening consecutive patients

– Data acquisition: Patients complete the CNS-LS, a validated PBA screening tool,2,3 and a QoL measure; demographic/disease characteristics are also collected; patient data are entered via the Web portal

AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; CNS-LS, Center for Neurologic Study–Lability Scale; IRB, Institutional Review Board; MS, multiple sclerosis; PBA, pseudobulbar affect; PD, Parkinson’s disease; PRISM, Pseudobulbar Affect Registry Series; QoL, quality of life; TBI, traumatic brain injury.

CONFIDENTIAL AND PROPRIETARY – AVANIR INC.

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Preliminary PRISM Data

PRISM REGISTRY DEMOGRAPHICSPatients 4575

Age (Mean) 65GENDER

Male 1791 39.15%Female 2784 60.85%PRIMARY DIAGNOSISALS 43 0.94%MS 1090 23.83%TBI 553 12.09%STR 645 14.10%PD 646 14.12%

AD 1598 34.93%

Total 4575 100.00%


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Preliminary PRISM Data

Current Percentage of Patients with CNS-LS score ≥13 = 37.9%*

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

ALS MS TBI STR PD AD

46.5% 46.2%

55.2%

37.4%

26.3%30.9%

ALS MS TBI STR PD AD

Total # of Pts = 4575


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CNS – Lability Scale

Total score: _________________

Applies never

Applies rarely

Applies occasionally

Applies frequently

Applies most of the time

1 2 3 4 5

Assessment questions Answers

There are times when I feel fine one minute, and then I’ll become tearful the next over something small or for no reason at all.

Others have told me that I seem to become amused very easily, or that I seem to become amused about things that really aren’t funny.

I find myself crying very easily.

I find that even when I try to control my laughter, I am often unable to do so.

There are times when I won’t be thinking of anything happy or funny at all, but then I’ll suddenly be overcome by funny or happy thoughts.

I find that even when I try to control my crying, I am often unable to do so.

I find that I am easily overcome by laughter.

A score of 13 or greater is indicative of clinical PBAMoore SR, et al. J Neurol Neurosurg Psychiatry. 1997;63(1):89-93.

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CNS-LS Score By Primary Neurological Condition

69.9%

30.1%

6.6%

46.3% 45.3%

26.8%

54.7%

74.6%

63.9%

47.1%

25.4%

36.1%

52.9%

11.2%

5.5%

9.0%

16.8%

53.7%


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Relationship between Con Meds and CNS-LS:AD only


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Relationship Between QOL* and CNS-LS

4.35

6.426.72

5.39

6.67

5.645.37

6.86

7.52

5.25

6.83

9.43

4.69

6.71

7.52

4.57

5.97

6.73

0.00

1.00

2.00

3.00

4.00

5.00

6.00

7.00

8.00

9.00

10.00

0 ‐ 12 13 ‐ 20 21 + 0 ‐ 12 13 ‐ 20 21 + 0 ‐ 12 13 ‐ 20 21 + 0 ‐ 12 13 ‐ 20 21 + 0 ‐ 12 13 ‐ 20 21 + 0 ‐ 12 13 ‐ 20 21 +

Alzheimer’s Disease Amyotrophic Lateral

Sclerosis

Multiple Sclerosis Parkinson’s Disease Stroke Traumatic Brain

Injury

Average QoL by Disease and CNS‐LS Score


*QOL scale 0-10; How is your QOL affected by your underlying neurologic condition

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NUEDEXTA Summary

• NUEDEXTA is the first and only FDA approved treatment for PBA

• In a controlled clinical trial, NUEDEXTA demonstrated clinically meaningful efficacy– Significantly reduced the frequency and severity of PBA episodes

– Over half of NUEDEXTA treated patients achieved episode remission

• NUEDEXTA was generally safe and well tolerated

• NUEDEXTA is indicated to treat all patients with PBA, regardless of underlying neurologic condition, unless otherwise contraindicatedPlease see Important Safety Information and full Prescribing Information provided today and available at www.NUEDEXTA.com.

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Questions?

44

BACK-UP SLIDES

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CNS-LS: A Validated Scale in PBA

Moore SR, et al. J Neurol Neurosurg Psychiatry. 1997;63(1):89-93.

Applies never

Applies rarely

Applies occasionally

Applies frequently

Applies most of the time

1 2 3 4 5

Assessment questions Answers

There are times when I feel fine one minute and then I’ll become tearful the next over something small or for no reason at all.

Others have told me that I seem to become amused very easily or that I seem to become amused about things that really aren’t funny.

I find myself crying very easily.

I find that even when I try to control my laughter, I am often unable to do so.

There are times when I won’t be thinking of anything happy or funny at all, but then I’ll suddenly be overcome by funny or happy thoughts.

I find that even when I try to control my crying, I am often unable to do so.

I find that I am easily overcome by laughter.

Total score: ________

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Underlying Conditions and Pseudobulbar Affect

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1. Work SS, et al. Adv Ther. 2011;28(7):586-601; 2. Newsom-Davis IC, et al. J Neurol Sci. 1999;169(1-2):22-25; 3. Gallagher JP. Acta Neurol Scand. 1989;80(2):114-117; 4. CaroscioJT, et al. Neurol Clin. 1987;5(1):1-8; 5. Ziegler LH. Arch Neurol Psychiatry. 1930;24(5):930-936; 6. Muller R. Acta Psychiatr Neurol Scand. 1952;27(1-2):137-156; 7. Gubbay SS, et al. J Neurol. 1985;232(5):295-300; 8. Kim JS. J Neurol. 2002;249(7):805-810; 9. Kim JS, et al. Neurology. 2000;54(9):1805-1810; 10. House A, et al. BMJ. 1989;298(6679):991-994; 11. Morris PL, et al. Aust N Z J Psychiatry. 1993;27(4):601-605; 12. Tang WK, et al. J Neurol. 2004;251(7):865-869; 13. Tateno A, et al. J Neuropsychiatry Clin Neurosci. 2004;16(4):426-434; 14. Zeilig G, et al. Brain Inj. 1996;10(8):591-597; 15. Pratt RT. J Neurol Neurosurg Psychiatry. 1951;14(4):326-335; 16. Feinstein A, et al. Arch Neurol. 1997;54(9):1116-1121; 17. Langworthy OR, et al. Am J Psychiatry. 1941;98:243-249; 18. Phuong L, et al. Parkinsonism Relat Disord. 2009;15(7):511-515; 19. Strowd RE, et al. J Neurol. 2010;257(8):1382-1387; 20. Petracca GM, et al. J Neuropsychiatry Clin Neurosci. 2009;21(4):406-412; 21. Siddiqui MS, et al. World J Biol Psychiatry. 2009;10(3):234-240; 22. Starkstein SE, et al. J NeurolNeurosurg Psychiatry. 1995;59(1):55-60; 23. Lopez OL, et al. Neuropsychiatry Neuropsychol Behav Neurol. 1996;9(3):154-161.

Estimated Prevalence of PBA in Neurologic Disorders

Neurologic Disorder Estimated Prevalence

Amyotrophic Lateral Sclerosis (ALS)1,2-7 2% - 53%

Stroke1,8-12 6% - 52%

Traumatic Brain Injury (TBI) 1,13-14 5% - 48%

Multiple Sclerosis (MS) 1,15-17 7% – 46%

Parkinson’s Disease (PD) 1,18-21 5% - 43%

Alzheimer’s Disease / Dementia1,22-23 9% - 39%

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47

Patient Videos

Crying Episode(Dementia Patient)

Crying Episode(Post Herpes Encephalitis Patient)

47

48

Proposed Mechanism of Action

• Pre-synaptic inhibition of glutamate release• Sigma-1 receptor agonism

• Post-synaptic inhibition of glutamate signaling• NMDA receptor antagonism

• Sigma-1 receptor agonism

1

2

NMDA, N-methyl-D-aspartate; R, receptor.NUEDEXTA™ (dextromethorphan hydrobromide and quinidine sulfate) capsules [prescribing information]. Aliso Viejo, CA: Avanir Pharmaceuticals, Inc; 2010.

Inhibition of glutamaterelease

Inhibition of glutamate signaling

Sigma-1 R NMDA R

Sigma-1 R

1

2

GlutamateDM

X

XThe mechanism by which NUEDEXTA exerts therapeutic

effects in patients with PBA is unknown.

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Underlying Conditions and Pseudobulbar Affect

Most Common

• ALS• Alzheimer’s disease • Multiple sclerosis• Parkinson’s disease• Stroke• Traumatic brain injury

Other Causes

• Brain tumors

• Brainstem AVM /

aneurysm

• CNS lipid storage

diseases

• Corticobasal

degeneration

• Frontotemporal

dementia

• Herpes encephalitis

• Hypoxic brain injury

• Neurosyphilis

• Normal pressure

hydrocephalus

• Primary lateral

sclerosis

• Progressive

supranuclear palsy

• Wilson’s disease

491. 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.

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