Poster # P3-290 / for Treatment of Pseudobulbar in Patients With : Examination of CNS-LS Outcomes in a 12-Week Open-Label Trial (PRISM II) Alzheimer’s Association International Conference Rachelle S. Doody, MD, PhD1; Stephen D’Amico, MD2; Andrew J. Cutler, MD3; Paul Shin4; Fred Ledon4; Charles Yonan, PharmD4; João Siffert, MD4 July 18-23, 2015 • Washington, DC, USA 1Baylor College of Medicine, Houston, TX; 2Cornerstone Medical Group, Franklin, TN; 3Florida Clinical Research Center, LLC, Bradenton, FL; 4Avanir Pharmaceuticals, Inc., Aliso Viejo, CA Introduction Figure 2. CNS-LS13 Figure 4. Primary Outcome, Change in CNS-LS Score (A) and Change in CNS-LS Figure 6. Change in CNS-LS Individual Item Scores • Pseudobulbar affect (PBA) is characterized by frequent, uncontrollable episodes of crying and/or laughing that are Instructions: Using the scale below, please write the number that describes the degree to which each item applies to you Laughing (CNS-LS-L) Subscore (B) and Crying (CNS-LS-C) Subscore (C) 6 exaggerated or incongruous with or social context1,2 DURING THE PAST WEEK. Write only one number for each item. A Baseline (n=108) Day 90/Final Visit (n=102) 25 CNS-LS CNS-LS Mean (SD) change Mean (SD) change Mean (SD) change Mean ( SD) change Mean ( SD) change Mean (SD) change Mean (SD) change

1–3 Applies never Applies rarely Applies occasionally Applies frequently Applies most of the time • PBA occurs when neurologic diseases or brain injuries damage neuronal pathways coordinating expression of affect –1.4 (1.3) –0.7 (1.2) –1.4 (1.4) –0.7 (1.2) –0.8 (1.4) –1.4 (1.3) –0.8 (1.2) 23 Mean (SD) change Mean (SD) change 5 • PBA episodes are disruptive, are often distressing, impair social function and quality of life (QOL), and may contribute to 1 2 3 4 5 –4.6 (5.1)* –7.2 (6.0)*

21 20.1 Score nursing home placement1,2,4 Assessment questions Answer 19

Item 4

LS LS Score

• Results of prevalence surveys suggest that approximately 6% to 10% of patients with Alzheimer’s disease or other 1. 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. - 3.6 * * * * * * *

17 3.5 LS have moderate to severe symptoms of PBA; however, PBA often goes unrecognized and may be mistaken for 2. Others have told me that I seem to become amused very easily or that I seem to become amused about things that really 15.5 - 3.2 2,3,5,6 15 or other psychiatric condition aren’t funny. 3 13.0 2.6 13 2.6 2.5 ® 2.3 • Dextromethorphan hydrobromide and quinidine sulfate (DM/Q; NUEDEXTA ) is the only treatment approved for PBA (FDA 3. I find myself crying very easily. 2.2 2.0 and EMA); approval was based on efficacy in patients with PBA secondary to amyotrophic lateral sclerosis (ALS) or 11 1.9

Mean (SD) CNS (SD) Mean 1.8 4. I find that even when I try to control my , I am often unable to do so. 2 1.7 1.8 1.8 (MS)7-9 9 5. 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 CNS (SD) Mean • This study (PRISM II) was conducted to provide additional DM/Q effectiveness, safety, and tolerability data in patient happy thoughts. 7 Baseline Day 30 Day 90/Final Visit 1 cohorts with PBA secondary to , traumatic brain injury, or dementia 6. I find that even when I try to control my crying, I am often unable to do so. (n=108) (n=108) (n=102) Fine one minute Amused very Cry very easily Unable to control Suddenly Unable to Easily 10 and tearful the easily laughter overcome by control crying overcome by • Final results from the dementia cohort have been previously presented ; we report here an additional analysis of the item 7. I find that I am easily overcome by laughter. next happy thoughts laughter distribution and response of the Center for Neurologic Study—Lability Scale (CNS-LS) scores, the primary effectiveness *P<.001, 1-sample t-test of absolute change in score from baseline measure Total Score: __ B 20 C 20 19 19 CNS-LS item scores each range from 1 to 5, with higher scores indicating increased frequency and severity of PBA episodes. 18 CNS-LS-L 18 CNS-LS-C CNS-LS=Center for Neurologic Study–Lability Scale; SD=standard deviation.

17 17 Methods 16 16 Results 15 Mean (SD) Mean (SD) change 15 Mean (SD) Mean (SD) Study Design Patient Disposition and Baseline Characteristics change –3.0 (4.1)* 14 change change Safety

L L Score 14

- C C Score 13 –1.9 (3.3)* - 13 –2.7 (3.3)* –4.2 (3.5)* • 49 (36.6%) patients reported 1 adverse event (AE; Table 2); most were mild to moderate in intensity

LS 12 - • Open-label, multicenter (~120 US sites), 12-week trial (NCT01799941) • 134 patients with PBA and dementia were evaluated for safety; 108 (81%) were included in effectiveness analyses; LS

12 - 106 (79%) completed the trial (Figure 3) 11 10.2 • AEs were considered at least possibly related to DM/Q treatment in 16 (11.9%) patients 11 9.9 10 Eligibility 10 • Patient characteristics are shown in Table 1 9 • Serious AEs occurred in 14 (10.4%) patients; none were considered treatment related by clinical investigators 11 12,13 9 8.1 8 7.5 • Adults with a clinical diagnosis of PBA and baseline CNS-LS score ≥13 8 7.1 7 6.0 • AEs led to study discontinuation in 16 (11.9%) patients • Clinical dementia diagnosis (Mini Mental State Examination [MMSE] score ≥10) 7 6

Figure 3. PRISM II Patient Disposition CNS (SD) Mean 6 Mean (SD) CNS (SD) Mean 5 • Stable doses (≥6 weeks) of dementia medications (memantine/cholinesterase inhibitors) or other neuropsychiatric 5 4 4 3 Table 2. AEs Occurring in ≥2% Patients medications (≥2 months) were allowed Completed: Enrolled (safety set)a: Early termination: Baseline Day 30 Day 90/Final Visit Baseline Day 30 Day 90/Final Visit (n=108) (n=108) (n=102) • No history of psychosis or delirium or contraindications to DM/Q; medical/neurologic condition stable and not rapidly N=134 n=28 n=106 (79.1%) (n=108) (n=108) (n=102) AE Category, n (%) Safety Population (n=134) changing *P<.001, 1-sample t-test of absolute change in score from baseline Headache 10 (7.5) Treatment Early termination due to (n=28): Urinary tract infection 6 (4.5) • All patients received DM/Q 20/10 mg twice daily (once daily during Week 1) • No postbaseline CNS-LS: n=16 Adverse event 14 (10.4%) CNS-LS scores range from 7 to 35, with higher scores indicating increased frequency and severity of PBA episodes. CNS-LS-L scores range from 4 to 20 and CNS-LS-C scores range from 3 to 15, with higher scores indicating increased frequency and severity. Diarrhea 5 (3.7) Assessments • Does not meet all eligibility criteria: n=10 Consent withdrawn 7 (5.2%) PBA=pseudobulbar affect; CNS-LS=Center for Neurologic Study–Lability Scale; SD=standard deviation. Nausea 3 (2.2) • Study visits and measures are shown in Figure 1. Caregivers completed ratings as proxies for patients who were unable Death 2 (1.5%) (except for MMSE) Fall 3 (2.2) Lack of efficacy 2 (1.5%) Figure 5. Distribution of Responses to CNS-LS Items at Baseline (n=108) Analyzed for Dizziness 3 (2.2) Figure 1. Study Visits and Outcome Measures effectivenessb: Lost to follow-up 2 (1.5%) 100 Somnolence 3 (2.2) n=108 (80.6%) Other 1 (0.7%) 3.7 6.5 Baseline Visit 1 Visit 2 Final Visit 11.1 6.5 AE=adverse event. Day 1 Day 30 Day 60 Day 90/Early Termination 90 22.2 Office Visit Office Visit Phone Visit Office Visit 26.8 14.8 30.6 26.9 a Safety analysis set consisted of all enrolled patients who received ≥1 dose of DM/Q. 80 19.4 bThe effectiveness analysis set includes patients who received ≥1 dose of DM/Q, had ≥1 postbaseline CNS-LS measurement, and met all eligibility criteria. Conclusions (%) CNS-LS=Center for Neurologic Study-Lability Scale. 70 39.8 Effectiveness Effectiveness Effectiveness Effectiveness 19.4 28.7 25.9 • PRISM II is the first clinical trial of PBA treatment in patients with dementia 60 25.9 1. CNS-LS 1. CNS-LS None 1. CNS-LS Table 1. Patient Characteristics—Safety Population (N=134) 26.9 26.9 2. PBA episode count 2. PBA episode count 2. PBA episode count • Patients with dementia who were taking DM/Q experienced significantly reduced PBA symptoms of both uncontrollable Safety 50 3. MMSE Safety 1. AEs 3. MMSE Characteristic n (%) Characteristic n (%) laughing and uncontrollable crying over this 12-week open-label trial 4. QOL-VAS 4. QOL-VAS 1. AEs 2. Concomitant meds Type of dementia 40 5. PGI-C/CGI-C Age 31.5 • Improvement in the CNS-LS (including overall score, laughing and crying sub-scores, and individual CNS-LS item scores) Safety 2. Concomitant meds Other 71 (12) Alzheimer’s disease 86 (64) 26.9 29.6 1. Patient medical history 3. Vital signs 6. Treatment satisfaction Mean, years (SD) 31.5 27.8 was accompanied by reductions in the number of PBA episodes/week and global improvements (PGI-C/CGI-C) 1. Assess compliance 58 (43) Vascular dementia 21 (16) 30 25.0 23.2 2. Concomitant meds Other Safety ≥75 years, n (%) Frontotemporal lobe dementia 12 (9) • DM/Q appeared well tolerated in this largely elderly population with dementia, with low rates of treatment-related AEs; AEs 3. Vital signs 1. PHQ-9 1. AEs Gender 55 (41) 20 Other 2. Assess compliance 2. Concomitant meds Male Lewy body dementia 5 (4) were consistent with DM/Q prescribing information a 14.8 of Respondents Percentage 16.7 12.0 1. PHQ-9 3. Vital signs Female 79 (59) Other 10 (7) 23.2 10 18.5 15.7 19.4 • Despite open-label limitations, reduction in overall CNS-LS scores were similar to that observed in the DM/Q phase 3 pivotal Other a Other dementia included dementia due to multiple sclerosis (n=4), Parkinson’s disease (n=1), alcohol-induced (n=1), brain cell deterioration (n=1), subcortical (n=1), 7.4 5.6 7.4 trial in patients with PBA secondary to ALS or MS, supporting the CNS-LS as a metric for assessing PBA symptoms and the 1. PHQ-9 unspecified (n=1), and mild cognitive impairment (n=1). SD=standard deviation. 0 1.9 2. Assess compliance Fine one minute Amused very Cry very Unable to control Suddenly Unable to control Easily effectiveness of DM/Q in PBA secondary to dementing conditions and tearful the next easily easily laughter overcome by happy crying overcome by CNS-LS: Overall and Laughing/Crying Sub-scores thoughts laughter References 1. Schiffer R, Pope LE. J Neuropsychiatry Clin Neurosci 2005;17:447-454. 2. Wortzel HS, et al. CNS Drugs 2008;22:531-545. 3. Work SS, et al. Adv AE=adverse event; CGI-C=Clinical Global Impression of Change; CNS-LS=Center for Neurologic Study-Lability Scale; MMSE=Mini Mental State Examination; Ther 2011;28:586-601. 4. Colamonico J, et al. Adv Ther 2012;29:775-798. 5. Brooks BR, et al. PLoS One 2013;8:e72232. 6. Yonan C, Foley K, Konetzka T. Alzheimer’s PBA=pseudobulbar affect; PGI-C=Patient Global Impression of Change; PHQ-9=Patient Health Questionnaire-9; QOL-VAS=quality-of-life visual analog scale. • Mean (SD) CNS-LS score reduction (i.e., improvement) was significant at Day 30 and Day 90/Final Visit (P<.001 for both; Applies most of the time Applies frequently Applies occasionally Applies rarely Applies never Figure 4A) compared with baseline Dement 2014;10(4):P911. 7. Brooks BR, et al. 2004;63:1364-1370. 8. Panitch HS, et al. Ann Neurol 2006;59:780-787. 9. Pioro EP, et al. Ann Neurol 2010;68:693-702. 10. Doody RS, et al. Presented at the 139th Annual Meeting of the American Neurological Association, Baltimore, MD, October 2014. 11. Cummings Statistical Analysis • The mean CNS-LS [SD] reduction from baseline (–7.2 [6.0]) was consistent with that seen for DM/Q in the phase 3 Percentages within an item may not sum to 100 due to rounding. JL, et al. CNS Spectr 2006;11:1-7. 12. Smith RA, et al. Mult Scler 2004;10:679-685. 13. Moore SR, et al. J Neurol Neurosurg 1997;63:89-93. CNS-LS=Center for Neurologic Study–Lability Scale. 9 • Primary analysis: Change from baseline in CNS-LS (1-sample t-test) for the effectiveness population that included patients pivotal trial (–8.2 [6.1]) and represents improvement over the change in the placebo group from that trial (–5.7 [5.3]) Support This study and presentation were funded by Avanir Pharmaceuticals, Inc. Editorial assistance was provided by Peloton Advantage, LLC, and was supported meeting eligibility criteria with postbaseline CNS-LS by Avanir Pharmaceuticals, Inc. • Significant improvement from baseline was seen for both CNS-LS laughing and crying subscores at Day 30 and Day Secondary Outcomes − The CNS-LS (Figure 2) is an established PBA rating instrument (range, 7–35) validated in patients with MS and 90/Final Visit (P<.001 for all; Figure 4B and 4C) Disclosures Rachelle Doody has consulted within the past 12 months for AbbVie, AC Immune, Avanir Pharmaceuticals, Inc., AZ Therapies, • Reduction in CNS-LS was consistent with reduction in PBA episode counts. Median (range) PBA episodes per week ALS11,12 and used as an outcome measure in DM/Q phase 3 trials7–9 • Mean (SD) baseline CNS-LS scores were higher for the 3 item CNS-LS-C (10.2 [3.0]) than for the 4 item CNS-LS-L Baxter, Biote, Cerespir, Chiesi, GlaxoSmithKline, Hoffmann-La Roche, Neurocog, Novartis, and Pfizer; has stock options in AZ Therapies, QR decreased from 21 (0, 90) at baseline to 6 (0, 77) at Day 30 and 3 (0, 80) at Day 90//Final Visit Pharma, Sonexa, and Transition; receives funding from the NIH Alzheimer’s Disease Cooperative Study and from the Texas Alzheimer’s − A planned analysis also compared the change in CNS-LS score in PRISM II with DM/Q pivotal phase 3 trial9 (9.9 [4.1]), indicating that pathologic crying symptoms were more common than pathologic laughing symptoms Research and Care Consortium; serves as principal investigator on clinical trials funded by Accera, Avanir Pharmaceuticals, Inc., Genentech, • Estimated PBA weekly episode counts were reduced by 50.2% at Day 30 and 67.7% at Day 90/Final Visit vs baseline Janssen Alzheimer Immunotherapy, NIH, Pfizer, and Takeda; and serves on the editorial boards of Alzheimer’s Research & Therapy and • This post-hoc exploratory analysis compares: change from baseline in CNS-LS Labile Laughter (CNS-LS-L) score (4 items, CNS-LS: Individual Item Scores (P<.001 for both; mixed-effects Poisson regression model) Dementia and Geriatric Cognitive Disorders. Stephen D’Amico has received honoraria as a consultant and speaker for Avanir Pharmaceuticals, range 4–20), CNS-LS Labile Crying (CNS-LS-C) score (3 items, range 3–15), and the 7 individual CNS-LS item scores • The distribution of baseline CNS-LS Item scores is presented in Figure 5 Inc.; has been a consultant and received research grants from AstraZeneca, Bristol-Myers Squibb, Merck, Novartis, Sanofi, and Takeda. Andrew • 77% and 76% of patients were deemed to be “much improved” or “very much improved” with respect to PBA Cutler has served as a consultant for, received research grants from, and served as a speaker for Abbott, AstraZeneca, Bristol-Myers Squibb, • All individual CNS-LS item scores improved significantly from baseline to Day 90/Final Visit (P<.001; Figure 6), with symptoms, based on clinician CGI-C, and patient or caregiver PGI-C ratings, respectively Forest, GlaxoSmithKline, Lilly, Merck, Novartis, Ortho-McNeil-Janssen, Otsuka, Pamlab, Pfizer, Shire, Sunovion, Takeda, and Vanda. Paul Shin, largest reductions for those items with higher baseline scores Fred Ledon, Charles Yonan, and Joao Siffert are employees of Avanir Pharmaceuticals, Inc.