In an echo of last month's disappointing closure of one arm of the Pfizer/Johnson and Johnson (Janssen AI) Phase III clinical trial of intravenous bapineuzumab, the companies have announced a discontinuation of the remaining studies. While scientists await full analysis of the results, some are suggesting that the complexity of the trial's design, and the complexity of the disease, might leave hope that variations of the trial could still be beneficial for some Alzheimer's patients.
Bapineuzumab was engineered to eliminate toxic amyloid beta from the brain by helping the body recognize the toxic protein and mobilize the immune system to remove it from the body. Amyloid beta is the primary component of the hallmark "plaques" that aggregate in the brains of Alzheimer's patients, although it also appears outside of plaques. Questions that linger include whether the bapineuzumab molecule appropriately engaged its target resulting in removal of amyloid beta from the brain. The trial design assessed cognitive changes in patients with mild to moderate Alzheimer's disease. In one scenario, the drug could have functioned as designed, but been unable to change cognitive performance because the underlying damage caused by the disease was too far advanced. If this is the case, administering this drug, or similar drugs, earlier in the course of the disease may have a much better chance of improving outcomes. The discontinuation covers only the intravenous version of bapineuzumab; other studies related to a subcutaneous administration are continuing for the time being.
Unfortunately, such trials tend to require many years and a significant investment. Despite the scientifically strong rationale, even the largest pharmaceutical companies have been hesitant to pursue this strategy. However, with the release of the bapineuzumab results, attention is shifting to three other trials that will assess both biomarker and cognitive performance early in the disease progression or preventative strategies in otherwise healthy patients. These trials include the ongoing DIAN, API, or the proposed "Anti-amyloid in treatment in Asymptomatic AD (A4)" trials. Depending on release of the bapineuzumab data, it is possible that bapineuzumab may actually be included in these trials where an earlier delivery of the drug might show stronger benefit to patients.
While no clear effect on cognitive decline of patients proved to be the downfall of the bapineuzumab trials, researchers are eagerly awaiting results of so‐called "biomarker" trials. Biomarkers are laboratory indicators of normally invisible biological processes. Earlier this year, two phase II trials of bapineuzumab showed that while spinal fluid amyloid beta levels did not fluctuate, there was reduction of another protein that is indicative of a different feature of Alzheimer's, the "neurofibrillary tangle." Formation of these tangles is correlated with reduction in cognitive performance. [Reference: Blennow et al 2012 Arch Neurol. http://www.ncbi.nlm.nih.gov/pubmed/22473769]
In the short‐term, while researchers consider the next steps for bapineuzumab and the possibility of early intervention, attention now turns toward Eli Lily and Baxter who have ongoing studies examining treatment of mild to moderate Alzheimer's disease patients. Lily's Solaneuzumab phase III trials are expected to release data in the next two months. Baxter's Gammagard recently reported success in a small phase II study.