Tetrabenazine Prestwick Pharmaceuticals, Inc. New Drug Application 21-894

1
TetrabenazinePrestwick Pharmaceuticals, Inc.
New Drug Application 21-894

• Peripheral and Central Nervous System Drugs
  Advisory Committee Meeting
• Beltsville, Maryland
• December 6, 2007
• Review of Safety
• Lourdes Villalba, M.D.
• Division of Neurology Drug Products (DNP)

Center for Drug Evaluation and Research
2
Overview

• Limitations of safety database
• Safety in study 004 and other studies
• Akathisia, parkinsonism,
• depression/suicidality dysphagia
• Other safety issues
• 100 vs. 50 mg/day
• Comments on Sponsors Proposed Risk Minimization
  Action Plan
• Summary

3
TBZ Safety DatabaseLimitations

• Small
• 111 unique subjects with HD in Prestwicks
  studies
• Flexible-dose design
• Titration up to desired effect, maximum dose of
  100 mg/day, or intolerable AEs over 7 weeks
• At the investigators discretion
• Complex disease
• Some of AEs associated with TBZ difficult to
  distinguish from underlying disease
• Depression dysphagia bradykinesia in late HD

4
NDA Database
Protocol Design N TBZ/Pla TBZ dose (mg/day) Sites
Prestwicks sponsored studies Prestwicks sponsored studies Prestwicks sponsored studies Prestwicks sponsored studies
004 007 R, DB, PC, 12 wks ? OL extension, 80 wks 54/30 75/0 12.5 100 12.5 200 16 16
005 006 R, DB, PC, staggered withdrawal, 5 days ? OL extension, 48 wks 30-24 29/0 Up to 150 Up to 150 1 1
Other data (Baylor studies) Other data (Baylor studies) Other data (Baylor studies) Other data (Baylor studies)
Chorea 011 Non-chorea OL, dose titration OL, compassion. use up to several years 1621 2802 12.5 200 12.5 - 200 1 1
R randomized DB double-blind PC
placebo-controlled OL open label N patients
randomized to TBZ. 1 Available for 98
patients with HD chorea and 47 with non-HD
chorea. 2 Available for 247 patients. Total
number of patients with HD exposed to TBZ in
Prestwick-sponsored studies 111.
Healthy subjects in clinical
pharmacology studies (n259) are not included.
5
TBZ Safety - Study 004 (I)
TBZ N54 n () Placebo N30 n ()
Death (suicide) 1 (1.9) 0
Non-fatal Serious AEs Breast cancer Fall/ subarachnoid hemorrhage Restlessness (Suicidal ideation/ paranoid psychosis) 3 (5.6) 0
Discontinuations due to AEs1 5 (9.2) 0
Dose reduction or stopping upward titration due to AEs 28 (52.0) 1 (3.3)

n Number of patients with AE. 1 Death
Serious AEs plus one case of akathisia.

6
TBZ Safety - Study 004 (II)
AEs that led to dose reduction or stopping upward titration TBZ N54 n () Placebo N30 n ()
All Sedation Akathisia Depression Parkinsonism Restlessness Anxiety Other 28 (52)1 15 (28) 5 (9) 3 (6) 4 (7) 2 (4) 2 (4) 2 (4)2 1 (3) 0 0 0 0 0 0 1 (3)3

n number of patients with AE. 1 Some patients
had more than one event. 2 Other one fatigue,
one diarrhea. 3 Dizziness.
7
AEs of Interest

• Akathisia, parkinsonism, depression and dysphagia
• Recognized as a potential drug-related AE?
• Dose related?
• Response to dose reduction?
• Effects on Total Chorea Scores (TCS)?

8
AE of Interest in Study 0041
TBZ (N54) n () TBZ (N54) n () Placebo (N30) n ()
Sponsor FDA2 Placebo (N30) n ()
Akathisia 5 (9) 7 (13) 0
Parkinsonism 5 (13) 8 (15) 0
Depression 8 (15) 10 (19) 0
Dysphagia 1 (2) 2 (4) 1 (3)
1 Source Adverse event concomitant medication
listings and UH file (Comments in the UHDRS
dataset, submitted 9/05). One patient may have
had more than one adverse event. 2 Cases not
included in sponsors analyses Two cases of
akathisia, one of parkinsonism and one dysphagia
recorded in UH file but not listed in AE listing
two additional cases from AE listings consistent
with parkinsonism one retrospective diagnosis of
depression in patient who committed suicide one
case of depression/paranoid psychosis/suicidal
ideation. Discrepancy points to difficulty in
ascertainment and coding.
9
AE of Interest in Studies 007 006
007 (multi-center) (N 75) 007 (multi-center) (N 75) 006 (single-center) (N 29) 006 (single-center) (N 29)
Sponsor n FDA n () Sponsor n FDA n ()
Akathisia 15 15 (20) - -
Parkinsonism 2 2 (3) 3 3 (10)
Depression1 24 26 (35) 9 10 (35)
Dysphagia2 3 6 (8) 3 3 (10)
N patients on TBZ. 1As per medication file 2
additional patients in 007 and one in 006 changed
their antidepressant regimen (dose increased,
antidepressant added or switched) to treat
depression, but were not recorded in AE listings.
3 Three additional cases of choking in the AE
listing for study 007.
10
AE of Interest in Studies 004, 007 006 - FDA
Analysis
004 (N54) n 007 (N 75) n 006 (N 29) n All (N111) Eventsa Patients()
Akathisia 7 15 - 22 20 (18)
Parkinsonism 8 2 3 13 13 (12)
Depression 10 26 10 51 44 (40)
Dysphagia 2 6 3 11 11 (10)
N patients on TBZ (total does not add up because
some patients in 004 rolled into 007). n
patients with event. a Events. A patient may have
the same event twice.
11
Akathisia, Study 004 (n7)

• Known to occur with other dopamine antagonists
• Sponsor identified 5 cases
• FDA identified 2 additional cases of Akathisia
• ID 236. Listed as restlessness in AE file
  recorded as akathisia in UH file 1
• ID 267. Not listed in AE listing mild akathisia
  recorded in UH file 1
• All on TBZ

1UH file containing United Huntingtons Disease
Research Score UHDRS) values and investigators
comments, submitted September 2005. There were 4
additional cases of restlessness in the AE
listings.
12
Akathisia, Study 004 (I)
ID TCSa Db 0 AE AE Dose reduction (DR) Yes/No Outcome Rd, Ce, WDf, NAg TCS After AEh TCS D 84i (dose)
ID TCSa Db 0 D Onset (dosec) D End Dose reduction (DR) Yes/No Outcome Rd, Ce, WDf, NAg TCS After AEh TCS D 84i (dose)
208 12 D 59 (100) D 92 No. R after C 12 16 (100)
229 14 D 19 (50) D 88 No. R after C 12 15 (100)
246 13 D 43 (100) D 71 Yes. ? Early WD, D 50 R after WD 6 NA
248 11 D 63 (75) D 63 Yes. R with DR. Recurred (007) 11 9 (37.5)
aTCS Total Chorea Score (Baseline dose 0). bD
relative day. cTBZ dose in mg/day. dResolved. eC
study completion. fWD withdrawal. gNA not
available. hTCS at next available visit.
iApproximate day for 12 week visit. Source
Sponsors tables. 248 had TCS on day 21 (50
mg/d) 6.
13
Akathisia, Study 004 (II)
ID TCSa D 0b AE AE Dose reduction (DR) Yes/No Outcome Rd, Ce, WDf, NAg TCS After AEh TCS D 84i (dose)
ID TCSa D 0b Onset (dosec) End Dose reduction (DR) Yes/No Outcome Rd, Ce, WDf, NAg TCS After AEh TCS D 84i (dose)
279 11 D 36 (75) D 38 Yes R with DR. Recurred (007) 8 9 (37.5)
236 20 40 (50) D 55 Yes j R with DR 10j 10 (37.5)
267 19 51 (62.5) - Nok Dose ? for sedation depression. Outcome of akathisia NA 12 8 (50)
aTCS Total Chorea Score (Baseline dose 0). bD
relative day. cTBZ dose in mg/day. dRResolved,
eWD withdrawal. fNA not available. g TCS at
next available visit. Italics not included in
sponsors analysis. j236, coded as restlessness
in AE file but recorded as akathisia in UH file.
TCS on Day 21 (50 mg/d) 11. k267 Akathisia not
in AE listing.
14
Summary of Akathisia in Study 004 (n 7, all TBZ)
Median Dose at onset (mg/d) 75 (range, 50-100) 75 (range, 50-100)
Median Time to onset (days) Median Time to onset (days) 43 (range,19-59)
Led to dose reduction (DR) or withdrawal (WD) Led to dose reduction (DR) or withdrawal (WD) n 4a n 1
Outcome Resolved after DR after completion after withdrawal Not available Outcome Resolved after DR after completion after withdrawal Not available n 3 (1 21 d) n 2 (4 - 12 d) n 1 (21 d) n 1 (not recorded as AE)
Patients with drop in TCS 3 at Week 12 2 out of 7 2 out of 7
Additionally, there were 4 cases of restlessness.
Some cases of restlessness may be difficult to
distinguish from akathisia.
15
Restlessness, Study 004 (II)
ID TCSa D 0b AE AE Dose Reduction (DR) Yes/No Outcome Rd, Ce, WDf,NAg TCS After AEh TCS D 84i (dose)
ID TCSa D 0b Onset (dosec) End Dose Reduction (DR) Yes/No Outcome Rd, Ce, WDf,NAg TCS After AEh TCS D 84i (dose)
213 19 D 48 (87.5) D 98 Yes. Hospitalized multiple medsj. R when TBZ stopped but recurred when TBZ restarted. WD for suicidal ideation psychosis on D 71. 10 NA
217 13 D 52 (100) D 75 Yes. R with DR 6 8 (87.5)
238 14 D 48 (100) D 68 Yes. R with DR 7 8 (75)
275 15 D 7 (37.5) D 7 No. R without DR 10 4 (100)
aTCS Total Chorea Score (Baseline dose 0). bD
relative day. cTBZ dose in mg/day. dDR dose
reduction. eResolved, fC completed. gD
withdrawal. hNA not available. i TCS at next
available visit. J Week 12 approximate day. j
Patient 213 received klonopin,
restoril, aprazolam, lorazepam, beta blockers,
bupropion, secobarbital and mirtazapine. Based on
BARNES scores, the sponsor agrees all 4 cases
are consistent with akathisia.
16
Parkinsonism, Study 004 (n8)

• Known to occur with dopamine antagonists also
  manifestation of late HD
• Sponsor identified 5 cases
• FDA identified 3 additional cases
• ID 231, Bradykinesia worse 1
• ID 233, Stiffness when walking2
• ID 240, Decreased dexterity, coordination
  abnormal,
• balance difficulty (along with
  dysphagia, dysarthria and
• insomnia) 2
• All on TBZ

1 Source UH file. 2 Source AE listings.
17
Parkinsonism, Study 004 (I)
ID TCSa D 0b AE AE Dose reduction (DR) Yes/No Outcome Rd, Ce, WDf, NAg TCS After AEh TCS D 84i (dose)
ID TCSa D 0b Onset (dosec) End Dose reduction (DR) Yes/No Outcome Rd, Ce, WDf, NAg TCS After AEh TCS D 84i (dose)
203 13 D 17 (50) D 90 No. Intensity ? to severe D 32 (TBZ 75mg/d). Dose ? for sedation. Intensity ? mod. D 56. R after C 7 9 (37.5)
207 16 D 28 (62.5) D 29 Yes. R with DR. 12 3 (25)
224 10 D 25 (62.5) - Yes. Ongoing at entry in 007 lost to FU on D 7 (admitted to NH facility) 7 7 (50)
236 20 D 18 (50) D 45 No. Dose ? to 37.5 mg/d because of disorientation sedation on D 23. R with DR. 11 10 (37.5)
263 10 D 50 (87.5) D 71 (Yes) R with DR. 0 4 (50)
18
Parkinsonism, Study 004 (II)
ID TCSa D 0b AE AE Drug Reduction (DR) Yes/No Outcome Rd, Ce, WDf,Nag TCS After AEh TCS D 84i (dose)
ID TCSa D 0b Onset (dosec) End Drug Reduction (DR) Yes/No Outcome Rd, Ce, WDf,Nag TCS After AEh TCS D 84i (dose)
231 19 D 36 (75) - No. Bradykinesia worse recorded in UH file. Dose ? for depression. Outcome NA (not recorded as AE) 9 12 (50)
233 20 D 36 (75) - No. Stiffness when walking and sedation. Outcome NA 19 22 (87.5)
240 15 D 29 (75) D 50 Yes. Coordination abnorm., balance difficulty, also fatigue, dysphagia, dysarthria insomnia. Most events R with DR on D 50. 18 17 (50)

• aTCS Total Chorea Score (Baseline dose 0). bD
  relative day. cTBZ dose in mg/day. dRResolved,
  eWD withdrawal. fNA not available. gTCS at next
  available visit. h Approximate day for 12 week
  visit. No ending date for event safer with
  rolling walker on D 63 TBZ up to 125mg/d in 007
  without reported AE of parkinsonism.

19
Summary Parkinsonism in Study 004 (n 8)
Median Dose at onset (mg/d) 62.5 (range, 50 - 87.5)
Median Time to onset (days) 28 (range, 17 36)
Led to dose reduction (DR) or Withdrawal n 4a n 0
Outcome Resolved after DR Resolved after Completion Not available n 4 (1 day 3 wks) n 1 (6 days) n 3 (1 lost to FU, 1 no end date for AE, 1 not in AE listing)
Patients with drop in TCS 3 at Wk 12 6 out of 8
a Additionally, 3 underwent dose reduction
because of other AEs (depression, sedation and
disorientation).
20
Additional Cases of Balance Difficulty, Study 004
(all on TBZ)
ID TCSa D 0b AE AE Dose reduction (DR) Yes/No Outcome Rd, Ce, WDf, Nag TCS After AEh TCS D 84i (dose)
ID TCSa D 0b Onset (dosec) End Dose reduction (DR) Yes/No Outcome Rd, Ce, WDf, Nag TCS After AEh TCS D 84i (dose)
223 16 D 38 (75) D 78 No. R without DR 14 11 (100)
237 15 D 45 (100) D 57 No. R without DR 8 5 (100)
313 12 D 39 (100) - No. Prominent incoordination, balance loss reported in UH file. Outcome NA 11 NA

• aTCS Total Chorea Score (Baseline dose 0). bD
  relative day. cTBZ dose in mg/day. dRResolved,
  eWD withdrawal. fNA not available. gTCS at next
  available visit. h
  Approximate day for 12 week visit.

21
Potential Extrapyramidal Symptoms (EPS) in study
004
AE Verbatim Term TBZ N54 n () Placebo N30 n ()
Akathisia (includes 2 in UH file) Bradykinesia (includes 1 in UH file) Slowness of movement Parkinsonism Stiffness when walking Dystonia Balance gait unsteady Poor coordination/gait unsteady Decreased dexterity/off balance Prominent incoordinat. balance loss Patients with any 7 2a 2 1 1 1 1 1 1 1 17 (32) 0 0 0 0 0 1 0 0 0 0 1(3)
a One patient had both akathisia and bradykinesia
22
Depression/Worsening Depression Study 004 (n10)

• Sponsor identified 8 cases
• FDA identified 2 more cases
• ID 271. Retrospective diagnosis based on signs
  of depression prior to suicide1
• ID 213. Patient discontinued for depression,
  suicidal ideation/psychosis, received treatment
  with mirtazapine2
• Although depression is prevalent in patients with
  HD, there were no treatment-emergent cases on
  placebo.
• Biological plausibility for increased risk of
  depression with TBZ (? dopamine, serotonin
  norepinephrine)

1 Source Narrative. 2 Source Concomitant
medication listing
23
Depression, Study 004 (I)
ID TCSa D 0b AE AE Dose reduction (DR) Yes/No Outcome Rd, Ce, WDf, NAg AD TCS After AEh TCS D 84i (dose)
ID TCSa D 0b Onset (dosec) End Dose reduction (DR) Yes/No Outcome Rd, Ce, WDf, NAg AD TCS After AEh TCS D 84i (dose)
206 14 D 4 (25) D 61 No. WD after fall SAH on D 31. R after WD Same 8 NA
228 11 D 62 (50) D 85 No. R with ? ? 6 8 (50)
229 14 D 82 (100) D 92 No. R after C None 15 15 (100)
231 24 D 24 (62.5) D 40 Yes. R with DR. Recurred (007) Same 7 12 (12.5)

• aTCS Total Chorea Score (Baseline dose 0). bD
  relative day. cTBZ dose in mg/day. dDR
  dose reduction. eResolved, fC completion
  gWD withdrawal. hNA not available. iTCS at next
  available visit. jApproximate day for 12 week
  visit. AD Antidepressant regimen. ? AD
  started, dose increased, switched,
  added.

24
Depression, Study 004 (II)
ID TCSa D 0b AE AE Dose reduction (DR) Yes/No Outcome Rd, Ce, WDf, NAg AD TCS After AEh TCS D 84i (dose)
ID TCSa D 0b Onset (dosec) End Dose reduction (DR) Yes/No Outcome Rd, Ce, WDf, NAg AD TCS After AEh TCS D 84i (dose)
244 12 D 50 (37.5) D 91 No. R after C ? 11 10 (37.5)
251 10 D 31 (75) D 62 Yes. R with DR and ? . ? 3 2 (12.5)
267 19 D 51 (62.5) D 58 Yes. Also had mild akathisia. R with DR. Suicide attempt in 007. Same 14 8 (50)
274 12 D 7 37.5 D 33 No. R with ? ? 12 8 (62.5)

• aTCS Total Chorea Score (Baseline dose 0). bD
  relative day. cTBZ dose in mg/day. dDR dose
  reduction. eResolved, fC completion gWD
  withdrawal. hNA not available. iTCS at next
  available visit. jApproximate day for 12 week
  visit. AD Antidepressant regimen. Changed
  AD started, dose increased, switched, added to
  prior Rx.

25
Depression, Study 004 (III)
ID TCSa D 0b AE AE Dose reduction (DR) Yes/No Outcome Rd, Ce, WDf, NAg AD TCS After AEh TCS D 84i (dose)
ID TCSa D 0b Onset (dosec) End Dose reduction (DR) Yes/No Outcome Rd, Ce, WDf, NAg AD TCS After AEh TCS D 84i (dose)
271 22 D 50 (87.5) - No. Retrospective Dx in patient who committed suicide. None 14 NA
213 19 D 69 (12.5) 72 No. Dose had been ? for restlessness. Early WD b/c suicidal ideation, depression, psychosis paranoid reaction on D 71. R with ? ? 9 NA
aTCS Total Chorea Score (Baseline dose 0). bD
relative day. cTBZ dose in mg/day. dResolved,
eC completion fWD withdrawal. gNA not
available. hhCS at next available visit.
iApproximate day for 12 week visit. AD
Antidepressant regimen. ? initiated
mirtazapine for indication of depression.
Patients ID 271 213 had no history of
depression.
26
Summary Depression in Study 004(n 10)
Median Dose at onset (mg/d) 62.5 (range, 25 100)
Median Time to onset (days) 50 (range, 4 82)
Dose reduction (DR) for depression Change in AD regimena n 3 n 5
Outcomeb Resolved with DR after completion after early WD with AD treatment with DR and AD treatment Did not resolve n 2 (1 to 2 wks) n 2 (1 wk) n 1c n 3d n 1 n 1e
Patients with drop in TCS 3 at Wk 12 5 out of 10
a AD antidepressant medication started,
increased, added or switched. b Two recurred in
007. c Early withdrawal because of fall and SA
hemorrhage (resolved 4 weeks after WD) d
Suicidal ideation resolved with AD treatment
(mirtazapine). e One patient committed suicide.
27
Dysphagia in Study 004

• Associated with TBZ at doses gt100 mg/day
• In study 004 sponsor identified one case on TBZ
  and one on placebo.
• FDA identified one additional case
• ID 224 occasional choking not listed as AE
  but recorded in UH file (on TBZ).

28
Dysphagia in Study 004
ID TCSa D 0b AE AE Dose reduction (DR) Yes/No Outcome Rd, Ce, WDf, Nag TCS After AEh TCS D 84i (dose)
ID TCSa D 0b Onset (dosec) End Dose reduction (DR) Yes/No Outcome Rd, Ce, WDf, Nag TCS After AEh TCS D 84i (dose)
240 15 D 23 (62.5) 61 Yes. R with DR. Also had dysarthria, balance diff. lethargy. Did not enter 007 17 17 (25)
224 10 D 32 (50) - No.j Outcome NA. Ongoing. Lost to FU on D 7 of 007 7 7 (50)
273 16 D 96 Placebo 96 No. R same day. Preceded by dyspepsia, N,V,Dk ulcerative stomatitis 14 14 Placebo
aTCS Total Chorea Score (Baseline dose 0). bD
relative day. cTBZ dose in mg/day. dResolved,
eC completion fWD withdrawal. gNA not
available. hTCS at next available visit.
iApproximate day for 12 week visit. j Choking
recorded in UH file but not AE listing. k N, V,
D nausea, vomiting, diarrhea.
29
Dysphagia in 004

• Small database, few cases
• Can not rule out detrimental effect of TBZ on
  dysphagia

30
Outcome for AE of InterestStudies 004, 007 006

• Recognized as a potential drug-related AEs by the
  investigator?
• Dose related?
• Effects on Total Chorea Scores (TCS)?

31
Outcome for AE of InterestStudies 004, 007 006

• Recognized as a potential drug-related AE?
• Not always
• Dose response for toxicity?
• Strong suggestion of a dose response
• Dose at onset of first event were (mg/day)
  50 (akathisia), 62.5 (parkinsonism),
  25 (depression) 50
  (dysphagia)
• Response to dose reduction or discontinuation?
• Yes, in general (unclear for depression
  dysphagia)
• Total Chorea Scores after dose reduction?
• In general, patients who had responded before
  developing the AE maintained a drop in TCS 3
  from baseline (if they did not discontinue TBZ).

32
Does TBZ 50 mg/day have a better
benefit/risk profile than 100 mg/day?Is there a
need to increase the dose to the point that
toxicity develops?
33
Number of Responders (TCS drop of 3) at Week
12, by dose Post-hoc exploratory analysis
Final dose All (N54) n () TCS drop 3 of patients on dose group
gt50 100 29 (54) 19 66
Up to 50 19 (35) 15 79
No data 6 (11) NA NA
Source Listing 1.2 Appendix 4 of Complete
Response (Feb 2007)
34
TCS Median Change (SE) from Baseline Over Time
By Responder Status at Week 12
1
0
-1
-2
-3
Delta TCS
-4
-5
-6
-7
-8
-9
35
TCS Median Change (SE) from Baseline Over Time
in Responders at Week 12
0
-1
-2
Responder gt 50-100 mg/d
Responder 50 mg/d
-3
-4
Delta TCS
-5
-6
-7
-8
-9
-10
Wk 3
Wk 7
Wk 12
36
Does TBZ 50 mg/day have a better
benefit/risk profile than 100 mg/day? Is there
a need to increase the dose to the point that
toxicity develops?

• Can not be answered in this database

37
Other Safety Issues

• Sedation
• Clearly dose related
• Falls
• No reduction as compared to placebo in 004
• Hyperprolactinemia
• Observed in clinical trials
• Neuroleptic Malignant Syndrome
• Postmarketing reports
• Hypotension/orthostatic hypotension
• Postmarketing reports
• QTc prolongation
• Positive TQTc study

38
Proposed Risk Minimization Action Plan (RiskMAP)

• RiskMAP
• A strategic safety program designed to meet
  specific goals and objectives in minimizing known
  risks of a product while preserving its benefits.
  
• Targets one or more safety-related health
  outcomes or goals
• Uses one or more tools to achieve those goals.
• Sponsor developed a plan to
• Address the risks of depression and
  restlessness/agitation
• Promote appropriate titration and dosing

39
Concerns regarding Sponsors RiskMAP Proposal

• Proposal is unlikely to be effective in
  minimizing the risk of serious depression/
  suicidality
• TBZ dose is titrated to intolerable adverse
  events (including depression) in addition to
  desired effect.
• No required monitoring by prescribing physician
• Monitoring and evaluation is being done over the
  telephone by an individual who may not be
  qualified

40
Risk Management Considerations

• Can the risk for depression and other adverse
  events be minimized?
• Are there actions, in addition to appropriate
  patient and prescriber labeling, that the sponsor
  could undertake to insure that tetrabenazine
  could be given safely?

41
TBZ Summary

• HD is a complex disease
• TBZ is effective in reducing TCS in patients with
  HD
• Safety profile consistent with other dopamine
  antagonists.
• Major Issues
• Depression/suicidality
• Extrapyramidal symptoms
• Difficult to recognize AEs as being drug-related

42
Acknowledgements

• Office of Surveillance Epidemiology, RiskMAP
  Review Team
• Mary Willy
• Claudia Karwoski
• Joyce Weaver
• Mary Dempsey
• Office of Clinical Pharmacology, Pharmacometrics
• Jogarao Gobburu
• Atul Bhattaram
• Sally Yasuda
• Division of Neurology Drug Products
• Alice Hughes
• Susan Daugherty
• Elizabeth McNeil
• John Feeney

43
Depression Baseline Risk Factors in Study 004
Measurement TBZ N54 Pla N30
Patients with Past Hx of depression () 34 (63) 14 (47)
Yes, Q 38 of UHDRS () 8 (15) 2 (7)
Mean HAM-D score SD (range) 4.5 3.4 (0-14) 5.1 3.9 (0-14)
Antidepressant use at baseline 30 (56) 20 (67)
Q 25 of UHDRS () 0 0
HAM-D 17-item Hamilton Depression scale UHDRS
Unified Huntingtons Disease Rating Scale.
Question 38 Does the investigator believe the
patient is depressed?. Q 25
suicidal ideation.
44
Depression Patients with recurrent event
ID 1st episode 1st episode 1st episode 2nd episode 2nd episode 2nd episode
Onset (day/dose) Action Resol (day) Onset (day/dose) Action Resol (day)
4-231 24 (62.5) DR 40 24 (62.5) DR 32
4-267 51 (62.5) DR 58 125 (62.5) DRAD WD1
7-209 145 (62.5) DRAD 359 535 (25) AD Ongoing
7-252 2 (12.5) AD 44 183 (25) AD 237
7-266 56 (75) AD 169 337 (50) AD Ongoing
7-288 50 (50) DRAD 182 355 (50) AD 5802
7-291 42 (87.5) DR 71 210 (75) None 5962
DR Dose reduction. AD change in antidepressant
regimen. WD withdrawal. Second episode
occurred in study 007. 1TBZ WD on D 463 because
of worsening depression. Psychosis with
depressive features started on D 466. Event
resolved on day 473.
2 Resolved after Week 80 (2-3
weeks after study completion date).
45
Narrative of Subject Who Committed Suicide in
Study 004

• ID 447-271. 40 y.o. male randomized to TBZ.
  Reported suicidal ideation in the past. No
  concomitant meds at the time of enrollment.
  Baseline TCS 22.
• At week 3 (TBZ 62.5 mg/d), TCS 14. Total HAM-D
  score was 0, including 0 suicidal thoughts.
• At week 7 (TBZ 87.5 mg/d), TCS was stable. HAM-D
  score was 1 due to early morning awakening.
• After this visit the patient decided to stop
  working because of his disability. Subsequently,
  his mood and behavior changed dramatically. He
  spent most of his time in his room at home and
  sometimes did not come out for meals. He
  committed suicide. The investigator judged that
  the AE was possibly related to study drug.

46
Narrative of Subject With Suicidal
Ideation in Study 004

• ID 447-213. 62 y.o. male randomized to TBZ. No
  prior history of depression. No concomitant meds
  at the time of enrollment. Baseline TCS 19.
• At week 3 (TBZ 50 mg/d), TCS 15.
• At week 7 (TBZ 100 mg/d), TCS 10.
• On Day 49 had restlessness, TBZ was suspended
  patient hospitalized. On D 56 he recovered from
  the event and re-started TBZ, 12.5 mg/day. Three
  weeks later, TBZ was not effective to control the
  chorea. He developed depression and suicidal
  thoughts, with symptoms of psychosis and
  paranoia, requiring hospitalization. Treated with
  mirtazapine, lorazepam and olanzapine. TBZ was
  d/c on Day 71. Symptoms resolved on Day 72. He
  was discharged on Day 79, to a nursing home
  facility. The event was considered by the
  investigator to be unrelated to TBZ.

47
Rate of Depression Patients with HD
Study/Duration N1 PYRs2 Number of events Rate per 100 PYRs
TBZ in Prestwicks studies TBZ in Prestwicks studies TBZ in Prestwicks studies TBZ in Prestwicks studies TBZ in Prestwicks studies
004/ 12 wks 54 12.2 10 82.0
007/ Up to 80 wks 75 96.8 26 26.9
006/ 48 wks 29 25.5 10 35.3
No TBZ No TBZ No TBZ No TBZ No TBZ
CARE-HD3 Up to 3 years 347 817.0 93 11.4
N patients randomized. 2 Person years of
exposure. CARE-HD Non-Prestwick study with
baseline characteristics similar to those in the
Prestwicks studies, with the following treatment
arms Remacemide, Co Q10, both, or placebo.
48
Rate of Dysphagia in Patients with HD
Study/Duration N1 PYRs2 Number of events Rate per 100 PYRs
TBZ in Prestwicks studies TBZ in Prestwicks studies TBZ in Prestwicks studies TBZ in Prestwicks studies TBZ in Prestwicks studies
004/ 12 wks 543 12.2 2 16.4
007/ Up to 80 wks 75 96.8 6 6.2
006/ 48 wks 29 25.5 3 11.8
No TBZ No TBZ No TBZ No TBZ No TBZ
CARE-HD4 Up to 3 years 347 817.0 32 3.9
N patients randomized. 2 Person years of
exposure. 3 Placebo 1 case, 14.3 per 100 PYRs.
4CARE-HD Non-Prestwick study with baseline
characteristics similar to those in the
Prestwicks studies, with the following treatment
arms Remacemide, Co Q10, both, or placebo.