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

VMAT2 Target for Hyperkinetic Movement Disorders Transaxial PET images depicting the preferential distribution of α -[C 11 ]-htbz at basal ganglia in a normal human subject. Koeppe et al., 1999 Kenney and Jankovic, 2006 The only approved medication targeting VMAT2 (Xenazine/Nitoman) has pharmacologic and pharmacokinetic profiles that result in a safety profile which limits clinical utility Tardive dyskinesia Schizophrenia Huntington’s chorea Tardive dystonia Tourette syndrome Dystonia

CYP2D6 PM CYP2D6 EMs NBI-98854: The Best in Class VMAT2 Inhibitor Current Option Not Appropriate for All Patients VMAT2-KiD2-Ki (+)-  -DHTBZ 1-4 nM >10  M (-)-  -DHTBZ 200 nM192 nM (+)-β-DHTBZ14 nM >10  M (-)-β-DHTBZ710 nM57 nM 1.Kilbourn, et al., Eur. J. Pharmacol, Mehvar, R. et al Drug Metabolism and Disposition Neurocrine Data Tetrabenazine (TBZ) (±)-  -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

Neurocrine’s Solution: Slow Systemic Release NBI ((+)  - DHTBZ ) (The active metabolite) NBI VMAT2-KiD2-Ki NBI (+)  -DHTBZ 1-4 nM >10  M NBI nM >10  M Potential advantages over approved therapies Reduced PK variability » qd dosing Improved side effect profile » Parent compound has low VMAT2 activity » The active metabolite is potent, has attenuated C max and is highly selective Very slow Inert

Single Ascending Dose Study NBI

Clinical Safety Summary NBI NBI generally safe and well tolerated No Serious Adverse Event (SAE) No clear Treatment Emergent Adverse Event (TEAE) trends or signal » No clinically significant ECG changes or QTcF prolongation » No clinically significant hemodynamic changes » Laboratory values unremarkable » No evidence of sedation, lethargy and somnolence Cog State testing : performance was stable across the study period when compared to placebo and baseline. 6

NBI-98854: Human PK at 75 mg C ONFIDENTIAL 7 NBI-98854NBI-98782

Human Exposure of the Active Metabolite NBI Compared with (±)  -Dihydrotetrabenazine C ONFIDENTIAL 8 Each circular dot represents an individual subject, and the horizontal lines represent the means for NBI after an oral dose of NBI (75 mg). The square dots bracket the range of concentrations of (±)α-DHTBZ that have been reported in the population of subjects taking 50 mg daily dose of tetrabenazine (FDA approval information for Xenazine ®.

NBI for hyperkinetic movement disorders: Product profile CxT comparison (±)α-DHTBZ vs. NBI Steady state simulation (75 mg NBI qd) Single, highly selective small molecule VMAT2 inhibitor Favorable safety and tolerability profile » Reduced Cmax » Selective: no off-target effects/pharmacology » Reduced PK variability » Predictable metabolism » Reduces need for dose titration QD dosing Novel small molecule Scalable manufacturing route Clinically proven MOA Single, highly selective small molecule VMAT2 inhibitor Favorable safety and tolerability profile » Reduced Cmax » Selective: no off-target effects/pharmacology » Reduced PK variability » Predictable metabolism » Reduces need for dose titration QD dosing Novel small molecule Scalable manufacturing route Clinically proven MOA