Pipeline Session: NBI-98854
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
Tardive dyskinesia
Schizophrenia
Huntington’s chorea
Tardive dystonia
Tourette syndrome
Dystonia
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
Transaxial PET images
depicting the preferential
distribution of α-[C11]-htbz at
basal ganglia in a normal
human subject.
Koeppe et al., 1999
NBI-98854: The Best in Class VMAT2 Inhibitor
Current Option Not Appropriate for All Patients
Tetrabenazine (TBZ)
(±)--DHTBZ
(Mix of 4 stereoisomers)
VMAT2-Ki
D2-Ki
(+)--DHTBZ
1-4 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
Neurocrine’s Solution: Slow Systemic Release
Inert
O
O
N
O
H
Very slow
OH
N
O
NBI-98854
H
OH
NBI-98782 ((+) -DHTBZ)
(The active metabolite)
VMAT2-Ki
D2-Ki
NBI-98782
(+) -DHTBZ
1-4 nM
>10 mM
NBI-98854
187 nM
>10 mM
Potential advantages over approved therapies
•
Reduced PK variability
»
•
qd dosing
Improved side effect profile
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»
Parent compound has low VMAT2 activity
The active metabolite is potent, has attenuated Cmax
and is highly selective
Single Ascending Dose Study
NBI-98854-0801
Period 1
Admit to
Center
Screening
< 27 days
Periods 2, 3 and 4 repeat
Discharge
from Center
D-1
D1
D2
D3
D4
D5
D6
D7
D8
etc
Study Rx
Pharmacokinetic samples at t=0 (predose),15, 30, and 45
min., 1, 1.25, 1.5, 2, 3, 4, 6, 8, 10, 12, 18, 24, 48, 72, 96
and 120h postdose
Final Visit: Day 28 (+ 2 days)
Cognitive State Test
Prolactin
12- lead ECG in Triplicate
Orthostatic Vital Signs
~30 days
Cohort
Cohort 2
Placebo / NBI-98854 Dose (mg)
1
Placebo
1
2
5
12.5
2
Placebo
12.5
25
50
75
~30 days
Cohort 1
Review of Safety and PK data prior start each Period
5
Clinical Safety Summary
NBI-98854-0801
• NBI-98854 generally safe and well tolerated
• No Serious Adverse Event (SAE)
• No clear Treatment Emergent Adverse Event (TEAE) trends or
signal
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»
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»
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
NBI-98854
NBI-98782
CONFIDENTIAL
7
Human Exposure of the Active Metabolite NBI-98782
Compared with (±) -Dihydrotetrabenazine
Each circular dot represents an individual subject, and the horizontal lines represent the means for NBI-98782 after an
oral dose of NBI-98854 (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®.
CONFIDENTIAL
8
NBI-98854 for hyperkinetic movement disorders: Product profile
CxT comparison
(±)α-DHTBZ vs. NBI-98782
 Single, highly selective small molecule
VMAT2 inhibitor
 Favorable safety and tolerability profile
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»
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»
Steady state simulation
(75 mg NBI-98854 qd)




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