Pipeline Session: NBI-98854

Selective Inhibitor of VMAT2 with an Attractive PK and Safety Profile for Hyperkinetic Movement Disorders

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

CYP2D6 PM

CYP2D6 EMs

NBI-98854: Rationale for Best in Class VMAT2 Inhibitor

VMAT2-Ki D2-Ki

(+)--DHTBZ 0.97 nM >10 M

(-)--DHTBZ 200 nM 192 nM

(+)-β-DHTBZ 14 nM >10 M

(-)-β-DHTBZ 710 nM 57 nM

1. Kilbourn, et al., Eur. J. Pharmacol, 19952. Mehvar, R. et al Drug Metabolism and Disposition 19863. 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

NBI-98854: Nonclinical characterization

In vitro pharmacology Potent VMAT2 inhibition >100-fold selectivity

In vivo pharmacology NE depletion (ptosis) Dopamine depletion (locomotor activity) Prolactin releaseDMPK 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

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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 MOA0

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SIMULATED human PK of NBI-98854 and NBI-98782 after single oral administration

of 25 mg NBI-98854

NBI-98854

NBI-98782