BARCELONA – An investigational anti-tau vaccine has passed its first big clinical milestone with a successful phase I trial of 30 patients with mild to moderate Alzheimer’s disease.
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The vaccine, AADvac-1, was safe and induced a robust immune response in the study. Patients who received the vaccine generally showed stable cognition over 6 months, although their trajectories were variable and the follow-up was short, Dr. Matej Ondrus said at the Clinical Trials in Alzheimer’s Disease conference.
The results in all three areas examined – safety, immunogenicity, and cognition – were good enough to propel AADvac-1 into aphase II study, scheduled for launch in early 2016, said Dr. Ondrus, medical director of Axon Neuroscience, the vaccine’s developer.
Dr. Ondrus refrained from overemphasizing the importance of such early cognitive findings. “We must stress that the variability was high and that this trial was not powered to show cognition. However, we did observe that cognition remained stable,” he said.
AADvac-1 is an active vaccine that targets neurofibrillary tau tangles. According to the company, it induces antibodies against a pathological conformation in the microtubule binding domain of diseased tau protein. An emerging body of evidence suggests that tau aggregation, rather than amyloid plaque formation, is directly linked to cognitive decline in Alzheimer’s. Only one other anti-tau vaccine, (ACI-35), is being investigated.
Patients in the phase I trial were randomized at four Austrian sites to either placebo (n = 6) or to the active vaccine (n = 24), in six monthly infusions. After 3 months of treatment, patients in the placebo arm crossed over to the active vaccine. Two patients dropped out, leaving 28 to finish the study. Of these, 25 have entered the 18-month follow-up study.
At baseline, patients were a mean age of 68 years and had a mean score of 20 on the Mini-Mental State Exam. Most (19) were taking an acetylcholinesterase inhibitor, including 11 in conjunction with memantine. One was on memantine monotherapy.
Infusion reactions were common, occurring in 43% of patients; 98% of these were mild.
There were five serious adverse events, all of them different. Two patients dropped out because of a serious adverse event, but only one – a viral infection followed by epileptic seizure – was judged as possibly related to the active vaccine.
There were three abnormal findings on brain imaging, Dr. Ondrus said. Two of these were expected brain changes for the study population and not reported as adverse events. The third finding was of two new microbleeds in a patient who had already experienced microbleeds at baseline. These were mild and not accompanied by any clinical symptoms, but nonetheless, were reported as an adverse event.
There were no differences seen on electrocardiogram and no physical manifestations of cardiovascular effects, he added.
AADvac-1 induced a robust immune response in 29 patients, which was seen after the second infusion and continued to mount thereafter. One patient reached maximum titer after two infusions; the rest reached it after six infusions. The average geometric mean titer after infusion six was 1:52,000.
The main cognitive endpoint was the Alzheimer’s Disease Assessment Scale–Cognitive Subscale. Dr. Ondrus showed data indicating that the vaccine was associated with a stabilizing of cognition, although the company did not conduct a statistical analysis of the data. He also noted that the company is looking for associations between cognitive results and individual antibody titer levels.
Only four patients contributed cerebrospinal fluid at baseline and study’s end, he added. Those samples are currently being analyzed.
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