TY - JOUR
T1 - Davunetide in patients with progressive supranuclear palsy
T2 - A randomised, double-blind, placebo-controlled phase 2/3 trial
AU - Boxer, Adam L.
AU - Lang, Anthony E.
AU - Grossman, Murray
AU - Knopman, David S.
AU - Miller, Bruce L.
AU - Schneider, Lon S.
AU - Doody, Rachelle S.
AU - Lees, Andrew
AU - Golbe, Lawrence I.
AU - Williams, David R.
AU - Corvol, Jean Cristophe
AU - Ludolph, Albert
AU - Burn, David
AU - Lorenzl, Stefan
AU - Litvan, Irene
AU - Roberson, Erik D.
AU - Höglinger, Günter U.
AU - Koestler, Mary
AU - Jack, Clifford R.
AU - Van Deerlin, Viviana
AU - Randolph, Christopher
AU - Lobach, Iryna V.
AU - Heuer, Hilary W.
AU - Gozes, Illana
AU - Parker, Lesley
AU - Whitaker, Steve
AU - Hirman, Joe
AU - Stewart, Alistair J.
AU - Gold, Michael
AU - Morimoto, Bruce H.
N1 - Funding Information:
SW, BHM, AJS, MGo, and LP were employees of Allon Therapeutics and JH was a paid contractor. AEL, MGr, DSK, RSD, LSS, ALe, and BLM were paid consultants for Allon Therapeutics. ALB received research support from Allon Therapeutics for enrolling participants and assistance with trial management in the form of a contract between Allon Therapeutics and the University of California, San Francisco, CA, USA. By contractual agreement with Allon Therapeutics, ALB, on behalf of the AL-108-231 steering committee (AEL, ALB, MGr, LSS, RSD, and ALe) took possession of all data and biological samples from the clinical trial. Additionally, ALB served as a consultant for Acetylon, Archer, Ipierian, Isis, and Neurophage and received research support from Bristol-Myers Squibb, C2N, Eli Lilly, Genentech, Janssen, Pfizer, and TauRx for doing clinical trials. He is funded by the National Institutes of Health (NIH), Alzheimer's Association, Bluefield Project to Cure Frontotemporal Dementia, CBD Solutions, and Tau Research Consortium. AEL has served as an adviser for Abbott, Abbvie, Allon Therapeutics, Avanir Pharmaceuticals, Biogen Idec, Boehringer-Ingelheim, Ceregene, Lilly, Medtronic, Merck, Novartis, NeuroPhage Pharmaceuticals, Teva, and UCB; received honoraria from Teva, UCB, and AbbVie; received grants from Brain Canada, Canadian Institutes of Health Research, Edmond J Safra Philanthropic Foundation, Michael J Fox Foundation, the Ontario Brain Institute, National Parkinson Foundation, Parkinson Society Canada, Tourette Syndrome Association, W Garfield Weston Foundation; received publishing royalties from Saunders, Wiley-Blackwell, Johns Hopkins Press, and Cambridge University Press; and served as an expert witness in cases related to the welding industry. DSK serves as the deputy editor for Neurology ; served on a data safety monitoring board for Lilly Pharmaceuticals; will serve on a data safety monitoring board for Lundbeck Pharmaceuticals and for the DIAN study; served as a consultant to TauRx Pharmaceuticals; was an investigator in clinical trials sponsored by Baxter and Elan Pharmaceuticals in the past 2 years; and receives research support from the NIH. BLM serves on a scientific advisory board for the Alzheimer's Disease Clinical Study; serves as an editor for Neurocase and as an associate editor of Alzheimer's Disease and Associated Disorders ; receives royalties from Cambridge University Press, Elsevier, and Guilford Press; serves as a consultant for Lundbeck, Elan Corporation, and Allon Therapeutics; serves on speakers' bureaus for Novartis and Pfizer; and receives research support from Novartis, NIH, and the State of California. RSD has received grant funds from NIH, and serves as a principal investigator on clinical trials for which her institution receives support from Accera, Avanir, Genentech, Pfizer, and Takeda. She has served as a consultant for Abbvie, Accera, AC Immune, Avanir, AZ Therapies, Baxter, Biote, Chiesi, Hoffmann-La Roche, Merck, Novartis, Targacept, and Toyama. She receives research support from the State of Texas. She has stock options in AZ Therapies, QR Pharma, Sonexa, and Transition, and serves on the editorial boards of Alzheimer's Disease Research and Therapy , and Dementia and Geriatric Cognitive Disorders . LSS has received grants from the NIH, the State of California, the Alzheimer's Association for a registry for dementia and cognitive impairment trials, and grants or research support from Baxter, Genentech, Johnson & Johnson, Eli Lilly, Lundbeck, Novartis, Pfizer, and TauRx. He has served as a consultant for and received consulting fees from Abbott Laboratories, AC Immune, Allon, AstraZeneca, Baxter, Biogen Idec, Biotie, Bristol-Myers Squibb, Chiesi, Elan, Eli Lilly, EnVivo, GlaxoSmithKline, Johnson & Johnson, Lundbeck, MedAvante, Merck, Novartis, Piramal, Pfizer, Roche, Sanofi, Servier, Takeda, Tau Rx, Toyama, and Zinfandel. J-CC received personal fees from Allon Therapeutics during the study and has received personal fees from Impax Laboratory, grants from Sanofi-Aventis, personal fees from Novartis, and personal fees from BIAL-Portela and Ca, Addex, and Lundbeck outside the submitted work. IG served on the board of directors of Allon Therapeutics until its purchase by Paladin Labs. The other authors declare no competing interests.
Funding Information:
The study was sponsored by Allon Therapeutics (Vancouver, BC, Canada), which was purchased by Paladin Laboratories in August, 2013. The study was designed by an academic steering committee in collaboration with the sponsor. The sponsor funded data gathering, the planned analyses, and an initial interpretation of the data. All authors had full access to the data, no medical writer or editor was employed, and the decision to submit the manuscript was made by the authors without input from any corporate entity. All authors had final responsibility for the decision to submit the paper for publication.
PY - 2014/7
Y1 - 2014/7
N2 - 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. Findings: 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%]). Interpretation: 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. Funding: Allon Therapeutics.
AB - 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. Findings: 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%]). Interpretation: 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. Funding: Allon Therapeutics.
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U2 - 10.1016/S1474-4422(14)70088-2
DO - 10.1016/S1474-4422(14)70088-2
M3 - Article
C2 - 24873720
AN - SCOPUS:84902545124
VL - 13
SP - 676
EP - 685
JO - The Lancet Neurology
JF - The Lancet Neurology
SN - 1474-4422
IS - 7
ER -