The recent failure of active immunotherapies targeting beta-amyloid in Alzheimer’s disease has dampened some of the initial enthusiasm for this approach. Development of AN1792, an active beta-amyloid vaccine, was terminated following the development of meningoencephalitis in 6% of vaccinated subjects. This complication was attributed to use of full-length beta-amyloid1-42.
Three second-generation vaccines, Affitope AD02, CAD106 and ACC-001, were then developed using shorter beta-amyloid fragments. A preliminary report of a phase II trial of Affitope AD02, which includes the B cell epitope but not the T cell epitope of beta-amyloid to minimize a Th1 response, indicated that the drug had not achieved its primary or secondary endpoints. Full data have not yet been published and its development status is unknown.
After some initial setbacks, ACC-001 (vanutide cridificar) reported some promising phase II results, but is no longer listed in the Pfizer pipeline.
For CAD106, the strategy of phase II studies has been to target early-stage AD. A rationale is that vaccination appears to be less effective at clearing vascular amyloid, so earlier treatment may prevent vascular impairment (Kokjohn & Roher. CNS Neurol Disord Drug Targets 2009;8:88-97; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC2742220/pdf/nihms129931.pdf).
However, targeting beta-amyloid has raised some concerns, notably that AN1792 was able to mobilize beta-amyloid from senile plaques but did not remove it from the brain (Patton et al. Am J Pathol 2006;169:1048–1063). Moreover, it has been suggested that mobilized beta-amyloid may deposit in the vasculature and white matter, which may have adverse consequences (Kokjon & Roher 2009).
One approach may be to combine CAD106 with a drug that inhibits BACE1 (beta-site amyloid precursor protein cleaving enzyme 1), which disrupts cleavage of amyloid precursor protein and beta-amyloid formation. A combination trial was announced in July 2014 in subjects at risk of developing AD (media release at www.novartis.com/newsroom/media-releases/en/2014/1824651.shtml).
To date, BACE1 inhibitors have had a mixed track record. A phase II trial of LY2886721 was terminated due to hepatotoxicity, although it is unclear if liver effects were related to its anti-BACE effects (Lahiri et al. Alzheimers Dement 2014;10(5 Suppl):S411-419). Development of RG7129 has been stopped. However, the EPOCH trial of MK-8931 has completed its interim safety analysis and has proceeded to phase III in patients with mild to moderate AD. A second study, APECS, in patients with prodromal AD began last November. Two other BACE inhibitors, AZD3293 and E2609, are in phase I testing.
Dr. Catherine Brodeur: Since the year 2000 and the failure of the AN1792 study, other trials involving active immunotherapy have been done with promising yet far from perfect results. As we now think that Alzheimer’s disease has a prolonged subclinical state (up to 15-20 years), we have seen more recent studies performed earlier in the disease process. Acting on two different steps of amyloid processing, deposition and clearance might also be a promising avenue. Finally, we cannot ignore that there is still debate on the most important pathophysiological mechanism of AD: beta-amyloid or tau?