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Pipeline Session: NBI-98854

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.

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Pipeline Session: NBI-98854

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  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. NBI-98854: Rationale for Best in Class VMAT2 Inhibitor (±)--DHTBZ (Mix of 4 stereoisomers) tetrabenazine CYP2D6 PM CYP2D6 EMs 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 Kilbourn, et al., Eur. J. Pharmacol, 1995 Mehvar, R. et al Drug Metabolism and Disposition 1986 Neurocrine Data

  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

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