# Presentation: 786674

## TetrabenazinePrestwick 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**** **

## 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 Sponsor’s Proposed Risk Minimization Action Plan
- Summary

## TBZ Safety DatabaseLimitations

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

##  NDA Database

| 
Protocol 
 | 
Design | 
N  
TBZ/Pla | 
TBZ dose
(mg/day)   | 
Sites |
| --- | --- | --- | --- | --- |
| Prestwick’s 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) |  |  |  |  |
| 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 (n=259) are not included.

## TBZ Safety - Study 004 (I)

** **

|  | TBZ
N=54 
n (%) | Placebo
N=30 
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.

## TBZ Safety - Study 004 (II)

** **

| AEs that led to dose reduction or stopping upward titration | TBZ
N=54 
n (%) | Placebo
N=30 
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.

## 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)?

## AE of Interest in Study 0041

|  | TBZ (N=54)
n (%) |  | Placebo 
(N=30)
n (%) |
| --- | --- | --- | --- |
|  | Sponsor | FDA2 |  |
| 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 sponsor’s 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.**

## AE of Interest in Studies 007 & 006

|  | 007 
(multi-center)
(N= 75)  |  | 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.

## AE of Interest in Studies 004, 007    & 006 - FDA Analysis

|  | 004 
(N=54)
n | 007 
(N= 75) 
n | 006
 (N= 29)
n | All 
(N=111)
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.

## Akathisia, Study 004 (n=7)

- 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

- 1“UH” file containing United Huntington’s Disease Research Score UHDRS) values and investigators’ comments, submitted September 2005. There were 4 additional cases of “restlessness” in the AE listings.

## Akathisia, Study 004 (I)

| ID# | TCSa
Db 0 | AE |  | Dose reduction (DR): Yes/No 
Outcome: Rd, Ce, WDf, NAg | TCS
After AEh | TCS
D 84i (dose) |
| --- | --- | --- | --- | --- | --- | --- |
|  |  | D Onset (dosec) | D
End |  |  |  |
| 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: Sponsor’s tables. * 248 had TCS on day 21 (50 mg/d)= 6.

## Akathisia, Study 004 (II)

| ID# | TCSa
D 0b  | AE |  | Dose reduction (DR): Yes/No 
Outcome: Rd, Ce, WDf, NAg | TCS
After AEh | TCS
D 84i (dose) |
| --- | --- | --- | --- | --- | --- | --- |
|  |  | Onset (dosec) | End |  |  |  |
| 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. dR=Resolved, eWD= withdrawal. fNA= not available. g TCS at next available visit. *Italics= not included in sponsor’s* *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.

## Summary of Akathisia in Study 004 (n= 7, all TBZ)

|  Median Dose at onset (mg/d) |    75 (range, 50-100) |  |
| --- | --- | --- |
|  Median Time to onset (days) |  |  43 (range,19-59) |
|  Led to dose reduction (DR) or 
   withdrawal (WD) |  |  n= 4a 
 n= 1 |
|  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 |  |

- Additionally, there were 4 cases of restlessness. Some cases of restlessness may be difficult to distinguish from akathisia.

## Restlessness, Study 004 (II)

| ID# | TCSa
D 0b  | AE |  | Dose Reduction (DR):  
   Yes/No 
Outcome: Rd, Ce, WDf,NAg | TCS
After AEh | TCS
D 84i (dose) |
| --- | --- | --- | --- | --- | --- | --- |
|  |  | Onset (dosec) | End |  |  |  |
| 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.

## Parkinsonism, Study 004 (n=8)

- 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 walking”2
- 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.

## Parkinsonism, Study 004 (I)

| ID# | TCSa
D 0b  | AE |  | Dose reduction (DR): Yes/No 
Outcome: Rd, Ce, WDf, NAg | TCS
After AEh | TCS
D 84i (dose) |
| --- | --- | --- | --- | --- | --- | --- |
|  |  | Onset (dosec) | End |  |  |  |
| 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) |

## Parkinsonism, Study 004 (II)

| ID# | TCSa
D 0b  | AE |  | Drug Reduction (DR):   
   Yes/No 
Outcome: Rd, Ce, WDf,Nag | TCS
After AEh | TCS
D 84i (dose) |
| --- | --- | --- | --- | --- | --- | --- |
|  |  | Onset (dosec) | End |  |  |  |
| 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. dR=Resolved, 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.

## 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).

## Additional Cases of Balance Difficulty, Study 004 (all on TBZ)

| ID# | TCSa
D 0b  | AE |  | Dose reduction (DR): Yes/No 
Outcome: Rd, Ce, WDf, Nag | TCS
After AEh | TCS
D 84i (dose) |
| --- | --- | --- | --- | --- | --- | --- |
|  |  | Onset (dosec) | End |  |  |  |
| 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. dR=Resolved, eWD= withdrawal. fNA= not available. gTCS at next available visit.                     h Approximate day for 12 week visit.

## Potential Extrapyramidal Symptoms (EPS) in study 004

| AE Verbatim Term | TBZ 
N=54
n (%) | Placebo
N=30
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

## Depression/Worsening Depression Study 004 (n=10)

- 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

## Depression, Study 004 (I)

| ID# | TCSa
D 0b  | AE |  | Dose reduction (DR): Yes/No 
Outcome: Rd, Ce, WDf, NAg | AD* | TCS
After AEh | TCS
D 84i (dose) |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  |  | Onset (dosec) | End |  |  |  |  |
|  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 Δ**  | Δ** | 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. ** Δ= AD               started, dose increased, switched, added.

## Depression, Study 004 (II)

| ID# | TCSa
D 0b  | AE |  | Dose reduction (DR): Yes/No 
Outcome: Rd, Ce, WDf, NAg | AD* | TCS
After AEh | TCS
D 84i (dose) |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  |  | Onset (dosec) | End |  |  |  |  |
| 244 | 12 | D 50
(37.5) | D 91 | No. R after C  | Δ** | 11 | 10
(37.5) |
| 251 | 10 | D 31
(75) | D 62 | Yes. 
R with DR and Δ** .  | Δ** | 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 Δ**  | Δ** | 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.

## Depression, Study 004 (III)

| ID# | TCSa
D 0b  | AE |  | Dose reduction (DR): Yes/No 
Outcome: Rd, Ce, WDf, NAg | AD* | TCS
After AEh | TCS
D 84i (dose) |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  |  | Onset (dosec) | End |  |  |  |  |
| 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 Δ** | Δ**
 | 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. ** Δ= initiated mirtazapine for indication of depression. Patients ID 271 & 213 had no history of depression.

## 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.

## Dysphagia in Study 004

- Associated with TBZ at doses >100 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).

## Dysphagia in Study 004  

| ID# | TCSa
D 0b  | AE |  | Dose reduction (DR): Yes/No 
Outcome: Rd, Ce, WDf, Nag | TCS
After AEh | TCS
D 84i (dose) |
| --- | --- | --- | --- | --- | --- | --- |
|  |  | Onset
(dosec) | End |  |  |  |
| 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 |

- Dysphagia in Study 004

- 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.

## Dysphagia in 004

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

## Outcome for AE of InterestStudies 004, 007 & 006

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

## Outcome for AE of InterestStudies 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).

## 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?

## Number of Responders (TCS drop of ≥3)  at Week 12, by dose Post-hoc exploratory analysis

| 
Final dose | All (N=54)
n (%)  | TCS drop ≥ 3 | % of patients on dose group |
| --- | --- | --- | --- |
| >50 – 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)

## TCS Median Change (±SE) from Baseline Over Time By Responder Status at Week 12

- -9

- -8

- -7

- -6

- -5

- -4

- -3

- -2

- -1

- 0

- 1

- Delta TCS

## TCS Median Change (±SE) from Baseline Over Time in Responders at Week 12

**TCS Median Change (****±****SE) from Baseline Over Time ****in Responders at Week 12**

- -10

- -9

- -8

- -7

- -6

- -5

- -4

- -3

- -2

- -1

- 0

- Responder > 50-100 mg/d

- Responder ≤ 50 mg/d

- Wk 3

- Wk 7

- Wk 12

- Delta TCS

## 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

## 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

## 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** **

## Concerns regarding Sponsor’s 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

## 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?

## 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

## 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

## Depression Baseline Risk Factors in Study 004

| Measurement | TBZ
N=54 | Pla
N=30 |
| --- | --- | --- |
| 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 Huntington’s Disease Rating Scale. Question 38: “Does the investigator believe the patient                  is depressed?”.  Q 25: suicidal ideation.

## Depression Patients with recurrent event

| ID | 1st 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) | DR+AD | WD1    |
| 7-209 | 145 (62.5) | DR+AD | 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) | DR+AD | 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).

## 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.

## 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.

## Rate of Depression Patients with HD

| Study/Duration | N1 | PYRs2 | Number of events | Rate per 
100 PYRs |
| --- | --- | --- | --- | --- |
| TBZ in Prestwick’s 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 |  |  |  |  |
| 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 Prestwick’s studies, with the following treatment arms: Remacemide, Co Q10, both, or placebo.

## Rate of Dysphagia in Patients with HD

| Study/Duration | N1 | PYRs2 | Number of events | Rate per 
100 PYRs |
| --- | --- | --- | --- | --- |
| TBZ in Prestwick’s 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 |  |  |  |  |
| 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 Prestwick’s studies, with the following treatment arms: Remacemide, Co Q10, both, or placebo.