Alistair Stewart

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

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.

Addressing Alzheimers Disease Tangles: From NAP to AL-108

AL-108 is the intranasal formulation of NAP (a peptide of eight amino acids, NAPVSIPQ). Phase IIa clinical results have recently shown that AL-108 has a positive impact on memory function in patients with amnestic mild cognitive impairment (aMCI), a precursor to Alzheimers disease (AD). The clinical development of AL-108 has been based on extensive studies showing pre-clinical efficacy for NAP. NAP has demonstrated potent neuroprotective activity in vitro and in vivo. Its mechanism of action is thought to center on the modulation of microtubule stability in the face of outside damage. Such an effect on structures of such central importance in a broad range of cellular functions is thought to explain NAPs activity in wide ranging models of cellular damage and neurodegeneration. The following article reviews NAPs discovery and pharmacological characterization that has led to clinical development of a novel tangle-directed drug candidate.

A pilot trial of the microtubule-interacting peptide (NAP) in mice overexpressing alpha-synuclein shows improvement in motor function and reduction of alpha-synuclein inclusions.

Abnormal accumulation of α-synuclein is associated with several neurodegenerative disorders (synucleinopathies), including sporadic Parkinsons disease (PD). Genetic mutations and multiplication of α-synuclein cause familial forms of PD and polymorphisms in the α-synuclein gene are associated with PD risk. Overexpression of α-synuclein can impair essential functions within the cell such as microtubule-dependent transport, suggesting that compounds that act on the microtubule system may have therapeutic benefit for synucleinopathies. In this study, mice overexpressing human wildtype α-synuclein under the Thy1 promoter (Thy1-aSyn) and littermate wildtype control mice were administered daily the microtubule-interacting peptide NAPVSIPQ (NAP; also known as davunetide or AL-108) intranasally for 2 months starting at 1 month of age, in a regimen known to produce effective concentrations of the peptide in mouse brain. Motor performance, coordination, and activity were assessed at the end of treatment. Olfactory function, which is altered in PD, was measured 1 month later. Mice were sacrificed at 4.5 months of age, and their brains examined for proteinase K-resistant α-synuclein inclusions in the substantia nigra and olfactory bulb. NAP-treated Thy1-aSyn mice showed a 38% decrease in the number of errors per step in the challenging beam traversal test and a reduction in proteinase K-resistant α-synuclein inclusions in the substantia nigra compared to vehicle treated transgenics. The data indicate a significant behavioral benefit and a long lasting improvement of α-synuclein pathology following administration of a short term (2 months) NAP administration in a mouse model of synucleinopathy.

Critical appraisal of the role of davunetide in the treatment of progressive supranuclear palsy

Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of tau protein aggregates in the basal ganglia, brainstem and cerebral cortex leading to rapid disease progression and death. The neurofibrillary tangles that define the neuropathology of PSP are comprised of aggregated 4R tau and show a well-defined distribution. Classically, PSP is diagnosed by symptoms that include progressive gait disturbance, early falls, vertical ophthalmoparesis, akinetic-rigid features, prominent bulbar dysfunction and fronto-subcortical dementia. There are currently no effective therapies for the treatment of this rapidly degenerating and debilitating disease. Davunetide is a novel neuroprotective peptide that is thought to impact neuronal integrity and cell survival through the stabilization of microtubules. Preclinical activity in models of tauopathy has been translated to clinical studies, demonstrating pharmacologic activity that has supported further development. Davunetide’s efficacy and tolerability are being tested in a placebo-controlled study in PSP patients, making it the most advanced drug candidate in this indication. This review examines the disease characteristics of PSP, the rationale for treating PSP with davunetide and assesses some of the challenges of clinical trials in this patient population.

Intranasal NAP (davunetide) decreases tau hyperphosphorylation and moderately improves behavioral deficits in mice overexpressing α-synuclein

Genome‐wide association studies have identified strong associations between the risk of developing Parkinsons disease (PD) and polymorphisms in the genes encoding α‐synuclein and the microtubule‐associated protein tau. However, the contribution of tau and its phosphorylated form (p‐tau) to α‐synuclein‐induced pathology and neuronal dysfunction remains controversial. We have assessed the effects of NAP (davunetide), an eight‐amino acid peptide that decreases tau hyperphosphorylation, in mice overexpressing wild‐type human α‐synuclein (Thy1‐aSyn mice), a model that recapitulates aspects of PD. We found that the p‐tau/tau level increased in a subcortical tissue block that includes the striatum and brain stem, and in the cerebellum of the Thy1‐aSyn mice compared to nontransgenic controls. Intermittent intranasal NAP administration at 2 μg/mouse per day, 5 days a week, for 24 weeks, starting at 4 weeks of age, significantly decreased the ratio of p‐tau/tau levels in the subcortical region while a higher dose of 15 μg/mouse per day induced a decrease in p‐tau/tau levels in the cerebellum. Both NAP doses reduced hyperactivity, improved habituation to a novel environment, and reduced olfactory deficits in the Thy1‐aSyn mice, but neither dose improved the severe deficits of motor coordination observed on the challenging beam and pole, contrasting with previous data obtained with continuous daily administration of the drug. The data reveal novel effects of NAP on brain p‐tau/tau and behavioral outcomes in this model of synucleinopathy and suggest that sustained exposure to NAP may be necessary for maximal benefits.

Looking for novel ways to treat the hallmarks of Alzheimer's disease.

Alzheimers disease (AD) represents an increasing public health issue as demographic changes and generally improved medical care result in a larger aged population. Although significant advances have been made in the diagnosis and treatment of AD, the unmet medical need remains and few treatment options are available. This review focuses on emerging therapies that aim to treat the underlying causes of the disease rather than the symptoms. Such disease-modifying treatments, focused on the two main hallmarks of the disease (plaques and tangles), include new and old targets which have significant potential in the field and are on the cusp of providing new treatment paradigms within the coming years.

Davunetide: a review of safety and efficacy data with a focus on neurodegenerative diseases.

Davunetide is the first neuroprotective peptide in its class, and has preclinical evidence for neuroprotective, neurotrophic and cognitive protective properties. Davunetide has also been shown to prevent apoptosis or programmed-cell death in a range of in vitro and in vivo models by promoting microtubule stabilization. Potential clinical uses of davunetide include neurodegenerative disorders such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD) or cognitive impairment in other diseases such as schizophrenia where microtubule structure and function is known to be impaired. The nonclinical and clinical safety of davunetide is reviewed here in detail. Pre-clinical toxicology studies in rats and dogs using the maximum feasible dose of davunetide provide strong evidence that davunetide is well-tolerated. Similarly, data from 10 separate clinical trials of davunetide, investigating safety and efficacy provide evidence that davunetide is generally safe and well-tolerated, and has shown some signs of clinical efficacy.