Background

Davunetide is an intranasal neuropeptide therapy derived from a growth factor called activity-dependent neurotrophic protein (ANAP). Released by glial cells, ANAP contains within it a peptide of the eight amino acids Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln. This peptide has highly potent neuroprotective activity. Published data supporting the rationale for its therapeutic potential range from reports on in-vitro neuroprotection against Aβ, viruses, and oxidative stress to neuroprotection in rodent models of stroke and hypoxia (see Jul 2002 news story). NAP is thought to modulate the pool of microtubules in neurons, but its exact mechanism of action is not clear. Inhibition of programmed cell death and correction of mitochondrial dysfunction also have been proposed as potential mechanisms.

NAP has been implicated in memory and cognition in mice. Genetic ANAP reduction impairs performance in the Morris water maze, and intranasal dosing with NAP was reported to reverse the effect. In a triple transgenic mouse model of AD, NAP reduced amyloid accumulation and tau hyperphosphorylation and improved performance in the Morris water maze (see Vulih-Shultzman et al., 2007; May 2007 news story; Matsuoka et al., 2008). NAP was reported to rescue a neuronal dysfunction phenotype in a fly model of tauopathy (see Quraishe et al., 2013).  

Other preclinical studies have reported beneficial effects of NAP in mouse models of amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) (see Jouroukin et al., 2013; Fleming et al., 2011).

Findings

Four Phase 2 and 3 clinical trials were conducted with a nasal spray formulation of davunetide.

From 2007–2008, a Phase 2 trial compared the effect on memory outcomes of 5 mg once a day, 15 mg twice a day, and placebo in 144 people with aMCI, frequently a prodrome to Alzheimer's disease.  This was a four-month, multicenter U.S. study. At conferences, the trial was reported to show a statistically significant improvement in test performance compared with placebo at eight weeks and 16 weeks, but not 12 weeks; a placebo effect was also mentioned. Safety data included headache and nasal irritation, but the drug was generally well-tolerated (see May 2008 news story; company release).

From 2007–2009, a Phase 2 trial compared two different doses of davunetide to placebo in 63 patients with chronic schizophrenia. In this trial, intranasal davunetide missed one coprimary outcome, the MATRICS composite battery of tests, but showed efficacy in the other, the University of California at San Diego performance-based skills assessment, UPSA. The treatment was also reported to show an effect on cortical thickness (see Javitt et al., 2012; Jarskog et al., 2013).

From 2010–2012, a one-year Phase 2/3 trial compared 30 mg of davunetide spray twice a day to placebo in 313 people with the tauopathy progressive supranuclear palsy (PSP). Coprimary outcomes were efficacy as measured by the Progressive Supranuclear Palsy Rating Scale (PSPRS) and the Schwab and England Activities of Daily Living Scale (SEADL), and safety. The trial included no measures of target engagement. Conducted at 47 sites in North America, Australia, and Europe, this pivotal trial was negative on all endpoints—primary, secondary, and exploratory.

This result halted clinical development of davunetide (see Dec 2012 news story; company press release). It also prompted a halt to recruitment into an ongoing safety and biomarker trial, begun in 2010, of davunetide in frontotemporal lobar degeneration (FTLD) with predicted tau pathology, corticobasal degeneration (CBS), or progressive supranuclear palsy (PSP). Results were formally published (Boxer et al., 2014).

For all clinical trials of Davunetide, see clinicaltrials.gov.

Davunetide was being developed by Allon Therapeutics based in Vancouver, Canada. Allon became insolvent and in July 2013 was acquired by the Canadian pharmaceutical company Paladin Labs (see YahooFinance story).

An intravenous formulation of davunetide exists, as well. Called AL-208, Allon tested this version of the drug between 2006 and 2008 in a Phase 2 trial of the safety and efficacy of a single 300-mg IV dose on cognitive impairment following coronary artery bypass surgery. Conducted in 234 cardiovascular patients, this trial has no published results; however, in a press release, claimed safety and tolerability for AL-208 as seen in a smaller Phase 1 study (see company press release).