Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial - 17/06/14

Doi : 10.1016/S1474-4422(14)70088-2

Adam L Boxer, DrMD ^a,^⁎ , Anthony E Lang, ProfMD ^b, Murray Grossman, ProfMD ^c, David S Knopman, ProfMD ^d, Bruce L Miller, ProfMD ^a, Lon S Schneider, ProfMD ^e, Rachelle S Doody, ProfMD ^f, Andrew Lees, ProfMD ^g, Lawrence I Golbe, ProfMD ^h, David R Williams, MD ⁱ, Jean-Cristophe Corvol, MD ^j,^k, Albert Ludolph, ProfMD ^l, David Burn, ProfMD ^m, Stefan Lorenzl, ProfMD ⁿ, Irene Litvan, ProfMD ^o, Erik D Roberson, MD ^p, Günter U Höglinger, ProfMD ^q, Mary Koestler, PhD ^a, Clifford R Jack, ProfMD ^r, Viviana Van Deerlin, MD ^s, Christopher Randolph, ProfPhD ^t, Iryna V Lobach, PhD ^a, Hilary W Heuer, PhD ^a, Illana Gozes, ProfPhD ^u, Lesley Parker, BSc ^v, Steve Whitaker, MD ^w, Joe Hirman, PhD ^x, Alistair J Stewart, PhD ^y, Michael Gold, MD ^z, Bruce H Morimoto, PhD ^aa

for the AL-108-231 Investigators^{^†}
Listed at end of paper

^a Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA

^b Department of Neurology, University of Toronto, Toronto, ON, Canada

^c Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA

^d Department of Neurology, Mayo Clinic, Rochester, MN, USA

^e 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

^f Department of Neurology, Baylor College of Medicine, Houston, TX, USA

^g Institute of Neurology, University College London, UK

^h Department of Neurology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA

ⁱ Faculty of Medicine, Monash University, Melbourne, VIC, Australia

^j Assistance Publique–Hôpitaux de Paris, INSERM, CIC1422 and UMRS1027, Sorbonne Universités, Université Pierre et Marie Curie, Paris, France

^k Department of Neurology, Pitié-Salpêtrière Hospital, Paris, France

^l Department of Neurology, University Hospital, Ulm, Germany

^m Institute for Ageing and Health, Newcastle University, Newcastle, UK

ⁿ Interdisciplinary Center for Palliative Medicine, Munich University Hospital-Klinikum Grosshadern, Munich, Germany

^o Department of Neurology, University of California, San Diego, CA, USA

^p Department of Neurology, University of Alabama, Birmingham, AL, USA

^q Department of Translational Neurodegeneration, Technical University Munich, Munich, Germany

^r Department of Radiology, Mayo Clinic, Rochester, MN, USA

^s Department of Neurology and Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

^t Department of Neurology, Loyola University School of Medicine, Chicago, IL, USA

^u 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

^v Tekmira Pharmaceuticals, Burnaby, BC, Canada

^w Omeros, Seattle, WA, USA

^x Pacific Northwest Statistical Consulting, Woodinville, WA, USA

^y Paladin Laboratories, St Laurent, QC, Canada

^z UCB BioSciences, Research Triangle Park, NC, USA

^aa Celerion, Lincoln, NE, USA

^* Correspondence to: Dr Adam L Boxer, Memory and Aging Center, Department of Neurology, University of California, San Francisco, Sandler Neurosciences Center, 675 Nelson Rising Lane, Suite 190, San Francisco, CA 94158-1207, USA

Summary

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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Vol 13 - N° 7

P. 676-685 - juillet 2014 Retour au numéro

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Davunetide in patients with progressive supranuclear palsy: a randomised, double-blind, placebo-controlled phase 2/3 trial - 17/06/14

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