View Part 1 on active immunotherapies

Monoclonal antibodies targeting beta-amyloid have produced a series of disappointments. Two phase III trials of bapineuzumab showed no significant effect on ADAS-cog or Disability Assessment for Dementia scores in patients with mild to moderate AD either with or without the APOE4 allele (Salloway et al. N Engl J Med 2014;370:322-333). A similar lack of efficacy was seen in the two phase III EXPEDITION studies of solanezumab (Doody et al. N Engl J Med 2014;370:311-321). Solanezumab is now being studied in patients with early-stage AD.

Results are now available for a phase II trial of crenezumab (Cummings J. Alzheimer Association International Conference; abstract 04-11-06). A total of 433 patients with mild to moderate AD were randomized to one of two doses of crenezumab (300 mg SC q2wks or 15 mg/kg q4wks) or placebo for 68 weeks. There was no benefit on cognitive decline or global function with either active regimen. However, in the subgroup with milder AD, there was a 35.4% reduction in cognitive decline and a 19.6% reduction in global functional decline. The next steps for crenezumab are unclear but it may join the ranks of treatments being examined in individuals at risk of developing AD or with prodromal  AD.

One issue, however, is that a recent laboratory study found that crenezumab had extensive cross-reactivity with non-beta amyloid proteins, and the authors suggested that it may not be a good candidate for drug development (Watt et al. Acta Neuropathol 2014;127:803-810).

Phase I studies have been completed with a fourth anti-amyloid MAb, gantenerumab (R1450), which raised concerns about amyloid-related imaging abnormalities (ARIA) (Ostrowitzki et al. Arch Neurol 2012;69:198-207). Ongoing phase III studies will investigate gantenerumab in mild AD, prodromal AD, and subjects at-risk of having an autosomal dominant AD mutation.

A slightly different approach is being explored with PF-04494700 (TTP488), a small-molecule inhibitor of the receptor for advanced glycation end products (RAGE). RAGE binds glycation end products, which cause inflammation and oxidative damage, but also binds beta-amyloid. However, a recent trial in mild to moderate AD found that the higher dose (20 mg/day) was associated with confusion, falls and greater ADAS-cog worsening (Galasko et al. Neurology 2014;82:1536-1542). There was some indication that the 5-mg dose slowed the decline in ADAS-cog scores at 18-month follow-up, however, there were no differences from placebo on other clinical or biomarker measures.

Comment
Dr. Catherine Brodeur: To try to avoid the deleterious side effects of active immunotherapy, multiple trials have been done involving passive immunotherapy in Alzheimer’s disease.  The advantage of this type of immunotherapy is, amongst others, that it does not engage the immune system of the individual, and therefore has a lower risk of T-cell activation-related side effects.  Unfortunately, other types of side effects or absence of clinical benefits were noted in recent studies on the ‘zumabs’.