1. Pipeline Session: NBI-98854 Selective Inhibitor of VMAT2 with an Attractive PK and Safety Profile for Hyperkinetic Movement Disorders

2. VMAT2 Target for Hyperkinetic Movement Disorders VMAT2 inhibition validated mechanism for symptom reduction of chorea, tardive dyskinesia, tics and other hyperkinetic movement disorders. Kenney and Jankovic, 2006 The only approved medication targeting VMAT2 has pharmacologic and pharmacokinetic characteristics that result in a safety profile which limits clinical utility. Transaxial PET images depicting the preferential distribution of α - [11c] htbz at basal ganglia in a normal human subject. Koeppe et al., 1999

3. CYP2D6 PM CYP2D6 EMs NBI-98854: Rationale for Best in Class VMAT2 Inhibitor VMAT2-KiD2-Ki (+)-  -DHTBZ 0.97 nM >10  M (-)-  -DHTBZ 200 nM192 nM (+)-β-DHTBZ14 nM >10  M (-)-β-DHTBZ710 nM57 nM 1.Kilbourn, et al., Eur. J. Pharmacol, 1995 2.Mehvar, R. et al Drug Metabolism and Disposition 1986 3.Neurocrine Data tetrabenazine (±)-  -DHTBZ (Mix of 4 stereoisomers) Human PK Current treatment regimen Suboptimal selectivity Unwanted stereoisomers confer poor selectivity Suboptimal pharmacokinetics Low bioavailability, high variability Polymorphic CYP2D6-dependent metabolism Requires dose titration bid or tid dosing regimen Side effects limit usefulness Depression, parkinsonism, akathisia

4. NBI-98854: Nonclinical characterization In vitro pharmacology  Potent VMAT2 inhibition  >100-fold selectivity In vivo pharmacology  NE depletion (ptosis)  Dopamine depletion (locomotor activity)  Prolactin release DMPK  Low drug interaction risk  PK in rats, dogs and monkeys In vitro genotoxicity  AMES  Chromosomal Aberration Safety pharmacology  CNS  hERG, in vivo QTc  Pulmonary Repeat dose toxicology  Rat  Dog √ √ √ √ √ √ √ √ √ √ √ √ √ √

5. NBI-98854 for hyperkinetic movement disorders: Product profile Reduced PK variability » Eliminates dose titration QD dosing likely Limited side effect profile » Reduced Cmax of the 45-fold potent active metabolite » Highly selective compound Novel small molecule Scalable route Phase I ready Clinically proven MOA