title: Lack of efficacy of L-759274, a novel neurokinin 1 (substance P) receptor antagonist, for the treatment of generalized anxiety disorder.
abstract: Preclinical studies suggest that substance P acting at neurokinin 1 (NK1) receptors may be involved in stress responses and NK1 receptor antagonists show activity in tests of anxiety. These data raise the possibility that NK1 receptor antagonists could be potential anxiolytic treatments in humans. We evaluated this hypothesis clinically using the NK1 antagonist L-759274. This is a randomized, double-blind, placebo- and active-controlled, multicentre, proof-of-concept trial. Patients with generalized anxiety disorder were randomized 1:1:1 to 6 wk of treatment with 40 mg L-759274 (n = 73), 1-6 mg lorazepam (n = 69) or placebo (n = 71). Efficacy was assessed using the Hamilton Anxiety Scale (HAMA). A positron emission tomography (PET) study was also performed in 16 healthy subjects to determine the relationship between NK1 receptor occupancy and plasma levels of L-759274 to verify adequate target engagement by the doses tested during the clinical trial. No statistically significant difference in mean change from baseline HAMA score at 6 wk was seen for L-759274 vs. placebo [difference = 1.0 (95% confidence intervals (CI) -1.2 to 3.2), p = 0.359] whereas the lorazepam group did show a significant improvement vs. placebo (difference = -2.7, 95% CI -5.0 to -0.4, p = 0.020) and L-759274 (difference = 3.7, 95% CI 1.5-6.0, p = 0.001]. Results from the PET study indicated that the L-759274 dosing regimen used in the clinical trial likely provided high levels of NK1 receptor occupancy (>90%), supporting the view that it was an adequate proof-of-concept trial. The NK1 receptor antagonist L-759274 does not appear to be efficacious for the treatment of generalized anxiety disorder.
authors.affiliation: Merck Sharp and Dohme Corp., Whitehouse Station, NJ, USA. david.michelson@merck.com
authors.forename: David
authors.initials: D
authors.lastname: Michelson
authors.forename: Richard
authors.initials: R
authors.lastname: Hargreaves
authors.forename: Robert
authors.initials: R
authors.lastname: Alexander
authors.forename: Paulette
authors.initials: P
authors.lastname: Ceesay
authors.forename: Jarmo
authors.initials: J
authors.lastname: Hietala
authors.forename: Christopher
authors.initials: C
authors.lastname: Lines
authors.forename: Scott
authors.initials: S
authors.lastname: Reines
mesh_terms: D000328:Adult; D014151:Anti-Anxiety Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001008:Anxiety Disorders / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000523:psychology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008140:Lorazepam / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D064729:Neurokinin-1 Receptor Antagonists; D049268:Positron-Emission Tomography / Q000379:methods; D016896:Treatment Outcome
chemical_list: D014151:Anti-Anxiety Agents; D064729:Neurokinin-1 Receptor Antagonists; D008140:Lorazepam