Background

This is an active vaccine designed to elicit an immune response against pathologically modified forms of tau protein. The approach was inspired by research on tau cleavage generating N-terminally truncated fragments (Feb 2013 news; Paholikova et al., 2015). 

The AADvac-1 vaccine consists of a synthetic peptide derived from amino acids 294 to 305 of the tau sequence, i.e., KDNIKHVPGGGS, coupled to keyhole limpet hemocyanin; the precise molecular nature of the antigen has not been disclosed. AADvac-1 uses aluminum hydroxide as an adjuvant. At the 2014 AAIC conference in Copenhagen, preclinical studies were reported as having met safety requirements for up to six months in rats, rabbits, and dogs; a paper reported that the vaccine reduced tau pathology and improved sensorimotor function in transgenic rats  (Aug 2014 news; Kontsekova et al., 2014).

Findings

In May 2013, Axon Neuroscience began a first-in-man Phase 1 trial at three sites in Austria to evaluate AADvac-1 in 30 patients with mild to moderate Alzheimer’s disease. Three subcutaneous, monthly injections of a single dose were assessed for safety, tolerability, and immunogenicity; some exploratory assessment of cognition was also done. A three-month, double-blind, randomized phase was followed by another three months of open-label observation for a total of six injections. After that, patients could enroll in a follow-up study lasting a further 18 months.

At the July 2015 AAIC conference, the company announced results. Twenty-four patients had been randomized to AADvac-1, six to placebo, according to Reinhold Schmidt of University of Graz. Two withdrew due to adverse events, of which one—a viral infection followed by epileptic seizure—was considered to be possibly related to the study medication. Overall, AADvac-1 in this study was safe and well-tolerated, Schmidt said. In a majority of participants, the vaccine induced increasing antibody titers with repeat injections. Mean ADAS-cog scores remained stable over six months.

In March 2016, a 24-month Phase 2 safety trial in mild to moderate AD began to enroll 185 patients with mild to moderate AD and an MRI consistent with this diagnosis. This trial is not ascertaining the presence of amyloid or tau pathology at study entry. The study compares eight subcutaneous injections of 40 microgram of vaccine with the adjuvant aluminum hydroxide to placebo. The primary outcome is safety; secondary outcomes include cognitive and clinical batteries as well a measure of immunogenicity. FDG PET, MRI volumetry, and CSF biochemistry constitute exploratory outcomes. This study lists 30 exclusion criteria. It is being conducted in Austria, the Czech Republic, Slovakia, and Sweden, and slated to run until February 2019.

For details on AADvac-1 trials, see clinicaltrials.gov. 

Clinical Trial Timeline