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.

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.

Copyright © 2014 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Atudy Profile

Figure 2. Change from baseline in primary outcome measures, the PSPRS and SEADL

(A) Least squares mean ± SEM change from baseline in PSPRS from primary ITT analysis. P = 0.41. An increase in PSPRS indicates worse disease. (B) Least squares mean ± SEM change from baseine in SEADL from primary ITT analysis. P = 0.92. A decrease in SEADL indicates worse performance.

Figure 3. Longitudinal change in CSF Nf-L correlated with imaging and clinical variables

Change in CSF neurofilament light chain concentration is correlated with (A) change in superior cerebellar peduncle volume measured on MRI (Spearman’s rho = −0.450, p = 0.045;n = 19) and (B) change in PSPRS oculomotor subscale (rho = 0.609; p = 0.003, n = 20). Blue circles: davunetide; black circles: placebo.