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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
NBI-98854: Rationale for Best in Class VMAT2 Inhibitor
tetrabenazine
(±)--DHTBZ
(Mix of 4 stereoisomers)
VMAT2-Ki
D2-Ki
(+)--DHTBZ
0.97 nM
>10 mM
(-)--DHTBZ
200 nM
192 nM
(+)-β-DHTBZ
14 nM
>10 mM
(-)-β-DHTBZ
710 nM
57 nM
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
1. Kilbourn, et al., Eur. J. Pharmacol, 1995
2. Mehvar, R. et al Drug Metabolism and Disposition 1986
3. Neurocrine Data
NBI-98854: Nonclinical characterization
In vitro pharmacology
√ Potent VMAT2 inhibition

√ >100-fold selectivity

In vitro genotoxicity
In vivo pharmacology
Safety pharmacology
√ NE depletion (ptosis)

√ Dopamine depletion (locomotor activity)

√ Prolactin release

DMPK
√ Low drug interaction risk

√ PK in rats, dogs and monkeys

√ AMES


√ Chromosomal Aberration
√ CNS

√ hERG, in vivo QTc

√ Pulmonary

Repeat dose toxicology
√ Rat

√ Dog

NBI-98854 for hyperkinetic movement disorders:
Product profile
• Reduced PK variability
» Eliminates dose titration
• QD dosing likely
• Limited side effect profile
SIMULATED human PK of NBI-98854 and
NBI-98782 after single oral administration
of 25 mg NBI-98854
Concentration (ng/mL)
70
NBI-98854
60
NBI-98782
» Reduced Cmax of the 45-fold
potent active metabolite
» Highly selective compound
50
40
30
20
10
0
0
6
12
Time (h)
18
24
•
•
•
•
Novel small molecule
Scalable route
Phase I ready
Clinically proven MOA