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

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.

Introduction

Progressive supranuclear palsy (PSP) is a neurodegenerative cause of atypical parkinsonism for which there are no approved or effective treatments.¹ At autopsy, insoluble aggregates of the microtubule-associated protein tau are found in neurons and glia throughout the brain, most prominently in the brainstem, deep cerebellar nuclei, and basal ganglia, with variable involvement of neocortical regions.2, 3 The most common clinical presentation of PSP, termed Richardson's syndrome, has a prevalence of about 6·5 cases per 100 000 individuals,⁴ and characteristically involves early and severe gait instability with falls, a greater slowing of vertical than horizontal saccadic eye movements that progresses to a supranuclear restriction of gaze, slowed movement, rigidity of the axial musculature, dysphagia, and pseudobulbar affect, along with variable neuropsychiatric abnormalities and dementia.

Genetically, PSP is strongly linked to the H1 tau gene (MAPT) haplotype and other single nucleotide polymorphisms within the MAPT gene.⁵ MAPT mutations that lead to inclusion of the alternatively spliced exon⁶ that contains one of the four potential microtubule-binding domains can lead to an autosomal dominant familial syndrome similar to PSP.⁷ A diagnosis of Richardson's syndrome is highly predictive of underlying PSP or related tau brain pathologies with predominantly four microtubule-binding repeat (4R) tau deposition,⁸ and therefore patients with PSP have been suggested to be an ideal population for testing of tau-directed or microtubule-directed treatments for neurodegenerative disease.⁹

Davunetide (AL-108, NAP) is the acetate salt of an eight aminoacid peptide (NAPVSIPQ) derived from activity-dependent neuroprotective protein, a growth factor released from glia in response to exposure to vasoactive intestinal peptide. In cell culture, davunetide has potent neuroprotective effects on cell death and microtubule disruption from a variety of toxic insults and in transgenic mice with one or more human MAPT mutations that typically lead to severe autosomal dominant disease, davunetide ameliorates deposition of hyperphosphorylated, insoluble forms of tau and improves performance on behavioural tests such as the Morris water maze.¹⁰ The results of a 12-week phase 2, randomised placebo-controlled clinical trial of davunetide administered intranasally to 144 individuals with amnestic mild cognitive impairment suggested potential treatment benefits on attention and working memory.⁶ Because executive function deficits, often involving working memory and attention, are common in PSP,¹¹ and on the basis of the proposed mechanism of action of davunetide, promoting stabilisation of microtubules and decreased tau pathology, we tested the hypothesis that davunetide would be an effective treatment for PSP in a multicentre, randomised, parallel group, double-blind, placebo-controlled trial. The primary objectives in the study were to assess the safety and efficacy of davunetide in slowing the rate of progression of the clinical features of PSP.