title: Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial.
abstract: BACKGROUND
  In preclinical studies, davunetide promoted microtubule stability and reduced tau phosphorylation. Because progressive supranuclear palsy (PSP) is linked to tau pathology, davunetide could be a treatment for PSP. We assessed the safety and efficacy of davunetide in patients with PSP.
  
  
  METHODS
  In a double-blind, parallel group, phase 2/3 trial, participants were randomly assigned with permuted blocks in a 1:1 ratio to davunetide (30 mg twice daily, intranasally) or placebo for 52 weeks at 48 centres in Australia, Canada, France, Germany, the UK, and the USA. Participants met the modified Neuroprotection and Natural History in Parkinson Plus Syndrome study criteria for PSP. Primary endpoints were the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England Activities of Daily Living (SEADL) scale at up to 52 weeks. All participants and study personnel were masked to treatment assignment. Analysis was by intention to treat. The trial is registered with Clinicaltrials.gov, number NCT01110720.
  
  
  RESULTS
  313 participants were randomly assigned to davunetide (n=157) or to placebo (n=156), and 241 (77%) completed the study (118 and 156 in the davunetide and placebo groups, respectively). There were no differences in the davunetide and placebo groups in the baseline PSPRS and SEADL. The davunetide and placebo groups did not differ in the change from baseline in PSPRS (median 11·8 [95% CI 10·5 to 13·0] vs 11·8 [10·5 to 13·0], respectively, p=0·41) or SEADL (-0·20 [-0·20 to -0·17] vs -0·20 [-0·22 to -0·17], respectively, p=0·92). 54 serious adverse events were reported in each of the treatment groups, including 11 deaths in the davunetide group and ten in the placebo group. The frequency of nasal adverse events was greater in the davunetide group than in the placebo group (epistaxis 18 [12%] of 156 vs 13 [8%] of 156, rhinorrhoea 15 [10%] vs eight [5%], and nasal discomfort 15 [10%] vs one [<1%]).
  
  
  CONCLUSIONS
  Davunetide is not an effective treatment for PSP. Clinical trials of disease-modifying treatment are feasible in patients with PSP and should be pursued with other promising tau-directed treatments.
  
  
  BACKGROUND
  Allon Therapeutics.
authors.affiliation: Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA. Electronic address: aboxer@memory.ucsf.edu.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Boxer
authors.affiliation: Department of Neurology, University of Toronto, Toronto, ON, Canada.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Lang
authors.affiliation: Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Murray
authors.initials: M
authors.lastname: Grossman
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Knopman
authors.affiliation: Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Department of Psychiatry and the Behavioural Sciences and Department of Neurology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
authors.forename: Lon S
authors.initials: LS
authors.lastname: Schneider
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Rachelle S
authors.initials: RS
authors.lastname: Doody
authors.affiliation: Institute of Neurology, University College London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lees
authors.affiliation: Department of Neurology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA.
authors.forename: Lawrence I
authors.initials: LI
authors.lastname: Golbe
authors.affiliation: Faculty of Medicine, Monash University, Melbourne, VIC, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Williams
authors.affiliation: Assistance Publique-Hôpitaux de Paris, INSERM, CIC1422 and UMRS1027, Sorbonne Universités, Université Pierre et Marie Curie, Paris, France; Department of Neurology, Pitié-Salpêtrière Hospital, Paris, France.
authors.forename: Jean-Cristophe
authors.initials: JC
authors.lastname: Corvol
authors.affiliation: Department of Neurology, University Hospital, Ulm, Germany.
authors.forename: Albert
authors.initials: A
authors.lastname: Ludolph
authors.affiliation: Institute for Ageing and Health, Newcastle University, Newcastle, UK.
authors.forename: David
authors.initials: D
authors.lastname: Burn
authors.affiliation: Interdisciplinary Center for Palliative Medicine, Munich University Hospital-Klinikum Grosshadern, Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lorenzl
authors.affiliation: Department of Neurology, University of California, San Diego, CA, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Litvan
authors.affiliation: Department of Neurology, University of Alabama, Birmingham, AL, USA.
authors.forename: Erik D
authors.initials: ED
authors.lastname: Roberson
authors.affiliation: Department of Translational Neurodegeneration, Technical University Munich, Munich, Germany.
authors.forename: Günter U
authors.initials: GU
authors.lastname: Höglinger
authors.affiliation: Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Koestler
authors.affiliation: Department of Radiology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.affiliation: Department of Neurology and Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Viviana
authors.initials: V
authors.lastname: Van Deerlin
authors.affiliation: Department of Neurology, Loyola University School of Medicine, Chicago, IL, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Randolph
authors.affiliation: Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: Iryna V
authors.initials: IV
authors.lastname: Lobach
authors.affiliation: Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA.
authors.forename: Hilary W
authors.initials: HW
authors.lastname: Heuer
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Adams Super Center for Brain Studies, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Illana
authors.initials: I
authors.lastname: Gozes
authors.affiliation: Tekmira Pharmaceuticals, Burnaby, BC, Canada.
authors.forename: Lesley
authors.initials: L
authors.lastname: Parker
authors.affiliation: Omeros, Seattle, WA, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Whitaker
authors.affiliation: Pacific Northwest Statistical Consulting, Woodinville, WA, USA.
authors.forename: Joe
authors.initials: J
authors.lastname: Hirman
authors.affiliation: Paladin Laboratories, St Laurent, QC, Canada.
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Stewart
authors.affiliation: UCB BioSciences, Research Triangle Park, NC, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gold
authors.affiliation: Celerion, Lincoln, NE, USA.
authors.forename: Bruce H
authors.initials: BH
authors.lastname: Morimoto
mesh_terms: D000368:Aged; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D009842:Oligopeptides / Q000009:adverse effects / Q000627:therapeutic use*; D013494:Supranuclear Palsy, Progressive / Q000175:diagnosis* / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D009842:Oligopeptides; C425904:davunetide