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 Sponsor’s Proposed Risk Minimization Action Plan • Summary

3. TBZ Safety DatabaseLimitations • 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

4. NDA Database R= randomized; DB= double-blind; PC= placebo-controlled; OL= open label; N= patients randomized to TBZ. 1 Available for98 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.

5. TBZ Safety - Study 004 (I) n= Number of patients with AE. 1 Death & Serious AEs plus one case of akathisia.

6. TBZ Safety - Study 004 (II) 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 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.

9. AE of Interest in Studies 007 & 006 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 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 (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.

12. Akathisia, Study 004 (I) 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.

13. Akathisia, Study 004 (II) 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’sanalysis. 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) • Additionally, there were 4 cases of restlessness. Some cases of restlessness may be difficult to distinguish from akathisia.

15. Restlessness, Study 004 (II) 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 (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.

17. Parkinsonism, Study 004 (I)

18. Parkinsonism, Study 004 (II) 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.

19. Summary Parkinsonism in Study 004 (n= 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) 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.

21. Potential Extrapyramidal Symptoms (EPS) in study 004 a One patient had both akathisia and bradykinesia

22. Depression/Worsening DepressionStudy 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

23. Depression, Study 004 (I) 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.

24. Depression, Study 004 (II) 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) 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.

26. Summary Depression in Study 004(n= 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 >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).

28. 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.

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 Source: Listing 1.2 Appendix 4 of Complete Response (Feb 2007)

34. Responder Non responder Wk 3 Wk 7 Wk 12 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. AE Requiring dose reduction TCS Median Change (±SE) from Baseline Over Time in Responders at Week 12 0 -1 -2 Responder > 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 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

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 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.

44. Depression Patients with recurrent event 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 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.

48. Rate of Dysphagia in Patients with HD 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.