Posted on 25 September 2016
One of the main hallmarks of Alzheimer’s disease is the clogging up of the brain with protein aggregates consisting of a protein known as amyloid-beta. This hallmark was already described by Dr. Alois Alzheimer, the physician who first described Alzheimer’s disease 110 years ago. In 1901 he observed a 51 year old woman named Auguste Deter in an asylum with behavioral and cognitive problems. Five years later she died and upon microscopic examination of brain preparations, dr. Alzheimer observed lesions that we now know were amyloid-beta plaques.
Antibodies are proteins produced by our immune system that are able to selectively recognize a wide diversity of targets – from other proteins to small molecules. Advances in biotechnology over the last two decades have enabled scientists to start exploring these antibodies as treatments for a wide diversity of diseases. More than a dozen antibody treatments against cancer have been approved, the most famous of which is herceptin (trastuzumab) for breast cancer.
Last year the FDA approved two antibody treatments that target PCSK9 for the treatment of atherosclerotic heart disease. Several antibody treatments are in clinical use for the treatment of rheumatoid arthritis, a degenerative inflammatory joint condition. Furthermore, antibody therapeutics against several autoimmune diseases, organ transplant rejection, age-related macular degeneration, and more are on the market or under development. Finally, multiple antibody treatments against Alzheimer’s disease have been developed in the last years (several examples will be discussed at the end).
Reported in the top journal Nature on September first are the results of the first human trial with a new anti-Alzheimer antibody named aducanumab. The trial named PRIME was a collaboration between the American biotech company Biogen (Massachusetts, US) and the Swiss biotech company Neurimmune (Schlieren-Zurich, Switzerland) with the Butler Hospital (Rhode Island, US) and the Institute for Regenerative Medicine (Zurich, Switzerland). The trial was a phase 1b placebo-controlled, double blind, and randomized clinical trial in 165 patients with early symptoms or mild Alzheimer’s disease. Starting therapy early in the disease may be very important and multiple failed studies with other interventions against Alzheimer’s disease may have failed because the patients were too far in the disease process. The goal of stage 1b trials is not to establish effectiveness (that’s the goal of later stage trials) but to establish safety and investigate the pharmacological properties of the drug (half-life time, distribution between organs, binding to the right target, and the like).
One year treatment with 3mg/kg, 6mg/kg or 10mg/kg all significantly reduced amyloid plaques in the brain of the human volunteers as determined by PET scans. The decrease was both dose- and time-dependent meaning that higher doses lea to greater reductions and that longer treatment period similarly lead to greater reductions. Treatment with aducanumab reduced brain amyloid in both ApoE ε4 carriers and non-carriers. ApoE ε4 is the largest genetic risk factor for senile Alzheimer’s disease (so not the inherited familial form).
In addition to the evidence that the treatment reduced amyloid-beta levels, the researchers also measured several clinical scores used to measure cognitive capacity. Treatment with aducanumab successfully delayed the worsening of cognitive function as measured by the Clinical Dementia Rating and the Mini Mental State Examination. However, it failed to delay the decline in memory as measured by other tests (Composite Neuropsychological Test and the Free and Cued Selective Reminding Test). Although it should be pointed out that the study was not designed to have enough subjects needed for powerful statistical evidence on the cognitive tests. After all phase 1 clinical trials are not designed to prove efficacy but merely safety and establish the pharmacological properties. In follow up phase II and phase III trials efficacy will be studied.
Aducanumab treatment appears safe with only minor side-effects such as headaches, urinary and respiratory-tract infections observed. The most-severe side effect were so called amyloid-related imaging abnormalities (or ARIAs for short). These are caused by the buildup of extracellular fluid in the brain and have been observed in previous antibody treatments for Alzheimer’s. They generally resolved within 12 weeks and no patient was hospitalized for them. 3 out of 118 patients developed anti-aducanumab antibodies within the first year of treatment but with low titers. This is a consequence of the immune system recognizing the Aducanumab antibody as a foreign substance and hence it starts to produce antibodies against it. Such antibodies could interfere with the action of Aducanumab and make these patients resistant to the treatment. Although in this trial the neutralizing antibodies did not seem to have an effect on the pharmacokinetics of Aducanumab. Follow up trials in which more patients are treated for longer periods of time should shed light on the potential for problems caused by these neutralizing antibodies.
Before starting human trials the investigators tested the antibody in mice engineered to develop Alzheimer’s disease. They could show that the antibody binds primarily to amyloid-beta fibrils and oligomers over monomers. It’s commonly believed that the oligomers are primarily responsible for causing the neurodegeneration seen in Alzheimer’s disease. The authors also showed that the antibody primarily bound to amyloid-beta in brain matter over amyloid-beta in blood vessels.
However we have to remain cautious about the result of this trial. Multiple monoclonal antibody treatments against Alzheimer’s have previously failed to find clinical benefits despite reducing amyloid-beta plaques. For example, two phase III clinical trials exploring the efficacy of the monoclonal anti-amyloid-beta antibody bapineuzumab in patients with mild to moderate Alzheimer’s disease did not meet the cognitive and functional endpoints. Another monoclonal anti-amyloid-beta antibody, solanezumab, failed in two phase III clinical trials in mild to moderate Alzheimer’s patients but showed some promising results in a subset of patients in a third phase III clinical trial.
Panza F, Logroscino G, Imbimbo BP, Solfrizzi V (2014). Is there still hope for amyloid-based immunotherapy for Alzheimer’s disease? Curr Opin Psychiatry 27(2): 128-137
Sevigny J et al. (2016). The antibody aducanumab reduces Abeta plaques in Alzheimer’s disease. Nature 537: 50-56