Tetrabenazine (Xenazine ® ) Prestwick Pharmaceuticals NDA Peripheral and Central Nervous System Drugs Advisory Committee Meeting Beltsville, Maryland December 6, 2007 Carole L. Davis, Clinical Reviewer, OND, DNP Peripheral and Central Nervous System Drugs Advisory Committee Meeting Beltsville, Maryland December 6, 2007 Carole L. Davis, Clinical Reviewer, OND, DNP Center for Drug Evaluation and Research

2 NDA Database NDA Database Protocol Design N TBZ/Pla TBZ dose (mg/day) Sites Prestwick’s sponsored studies R, DB, PC, 12 wks  OL extension, 80 wks R, DB, PC, staggered withdrawal, 5 days  OL extension, 48 wks 54/30 75/ / – – 200 Up to Other data (Baylor studies) Chorea – 011 Non-chorea OL, dose titration OL, compassion. use up to several years – 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.

3 UHDRS & FIS Assessments (baseline to aver. wks ) Endpoint TBZ Placebo p-value ANCOVA Total Motor Score T Total Chorea Score <0.001 T Gait Score T Cognition Score* Exp P Behavioral Assessment (BA) Exp P Functional Assessment (FA) P Independence Scale (IND) Exp P Functional Capacity (TFC)* Exp P Functional Impact Scale (FIS)* T= favors TBZ. P= favors Placebo. * = Wk. 12 data only

4 Subject-Oriented Assessments Question 79 (UHDRS) – Week 13 Visit Since your last assessment, does the participant feel: 1 = improved, 2 = worsened, 3 = about the same, 4 = N.A. CGI – Part 2 (Global Improvement): Compared to baseline, rate total improvement whether or not, in your judgment, it is due entirely to drug. (1 = normal, 7 = very much worse) CGI – Part 1 (Severity of Illness): Considering your total clinical experience with this particular population, how ill is the patient at this time? (1 = normal, 7 = among the most extremely ill patients) CGI – Part 3 (Efficacy Index): Rate on the basis of drug effect only – select the terms that best describe the degrees of therapeutic effect and side effects and record the number in the box where the two items intersect. Question 79 (UHDRS) – Week 13 Visit Since your last assessment, does the participant feel: 1 = improved, 2 = worsened, 3 = about the same, 4 = N.A. CGI – Part 2 (Global Improvement): Compared to baseline, rate total improvement whether or not, in your judgment, it is due entirely to drug. (1 = normal, 7 = very much worse) CGI – Part 1 (Severity of Illness): Considering your total clinical experience with this particular population, how ill is the patient at this time? (1 = normal, 7 = among the most extremely ill patients) CGI – Part 3 (Efficacy Index): Rate on the basis of drug effect only – select the terms that best describe the degrees of therapeutic effect and side effects and record the number in the box where the two items intersect.

5 Clinical Global Impression Scales (Study 004): Adjusted Mean Change from Baseline to Week 12 (LOCF) Clinical Global Impression Endpoint TBZ Placebop-value ANCOVA Difference Numerically Favors CGI – Part 2 Global Improvement TBZ CGI – Part 1 Disease severity Exp Unchanged CGI – Part 3 Efficacy index Exp <0.001TBZ

6 CGI – Part 3 (Efficacy Index) Therapeutic Effect Side Effects (Scores: TBZ = 3.00, Placebo = 3.75) NoneNot sig. interfering with function Sig. interferes with function Outweighs therapeutic effect Marked Moderate Minimal- Slight Unchanged or Worse

7 Mean Change in Functional Parameters Baseline to Week 12 Mean Change in Functional Parameters Baseline to Week 12 Functional Scale (Range of Scores) Change with Improvement Change TBZ Change Placebo p-value test ANCOVA Difference Numerically Favors Functional Assessment Checklist (FA) 0*-25 ↑ Placebo Independence Scale (IND) 10*-100 ↑ Placebo Total Functional Capacity (TFC) 0*-13 ↑ Placebo Functional Impact Scale (FIS) 0-15* ↓ Unchanged

8 Change from Baseline to Week 12 in Selected ADL Items TBZ Placebo ADL DECLINED N (%) UNCHANGED N (%) IMPROVED N (%) DECLINED N (%) UNCHANGED N (%) IMPROVED N (%) Prepare meal 4 (7.4)47 (87.0)3 (5.6)1 (3.3)26 (86.7)0 (0.0) Telephone6 (11.1)46 (85.2)2 (3.7)0 (0.0)30 (100)0 (0.0) Meds with- out help 4 (7.4)48 (88.9)2 (3.7)0 (0.0)30 (100)0 (0.0) Feed self2 (3.7)51 (94.4)1 (1.9)1 (3.3)29 (96.7)0 (0.0)

9 Change from Baseline to Week 12 in Mobility/Transfer ADL Items TBZPlacebo ADL DECLINED N (%) UNCHANGED N (%) IMPROVED N (%) DECLINED N (%) UNCHANGED N (%) IMPROVED N (%) Walk with- out falls 3 (5.6)48 (88.9)3 (5.6)0 (0.0)29 (96.7)1 (3.3) Walk with- out help 0 (0.0)53 (98.1)1 (1.9)0 (0.0)30 (100)0 (0.0) Chair-chair Transfers 0 (0.0)54 (100)0 (0.0) 30 (100)0 (0.0) In/out of bed 0 (0.0)54 (100)0 (0.0) 29 (96.7)1 (3.3) Use toilet0 (0.0)54 (100)0 (0.0) 29 (96.7)1 (3.3)

10 Cognition Test (UHRDS Part II) Baseline to Week 12 Cognition Test - (UHRDS II): TBZPlacebo p-value ANCOVA Difference Numerically favors Total Cognitive Score Placebo Verbal Fluency Test Placebo Symbol Digit Modalities Test Placebo Stroop Test (3-part) Placebo

11 Summary/Conclusions:Summary/Conclusions: NDA tetrabenazine for the treatment of the chorea of Huntington’s disease showed statistical significance for the reduction of chorea (the study’s primary endpoint) but failed to show significant evidence of other efficacy benefits. Re-analysis by the sponsor did not show any substantial changes. Difficulty in clarifying efficacy benefits for a risk- benefit analysis for the drug. NDA tetrabenazine for the treatment of the chorea of Huntington’s disease showed statistical significance for the reduction of chorea (the study’s primary endpoint) but failed to show significant evidence of other efficacy benefits. Re-analysis by the sponsor did not show any substantial changes. Difficulty in clarifying efficacy benefits for a risk- benefit analysis for the drug.