Symptom reduction
Results showed a reduction in the progression of symptoms in the plasma exchange–treated patients for both primary endpoints.
The ADCS-ADL showed 52% less decline in the plasma exchange–treated group, compared with the placebo group (P = .03); the ADAS-Cog showed 66% less decline (P = 0.06). In the moderate group, both endpoints showed 61% less decline (P = .002 and .05, respectively).
There were no clear differences between the three active-treatment groups, “suggesting that any of them could be considered for further investigation,” said Dr. Páez.
Differences in baseline demographic characteristics did not appear to have an influence on the outcomes. ADAS-Cog was more than twice as effective as some candidate monoclonal antibodies targeting Abeta that are being investigated for Alzheimer’s disease, Dr. Páez noted.
Although the plasma exchange approach is relatively invasive, so too are monoclonal antibody therapies that are infused intravenously through a pump, he said. In addition, a low-volume plasma exchange maintenance treatment takes less than 2 hours, which is on a par with some monoclonal antibody treatments.
Key secondary outcomes
For both primary outcomes, changes were found in those with moderate but not mild Alzheimer’s disease, possibly because the ADAS-Cog was designed for patients with more severe symptoms and may not be sensitive enough for patients with better cognitive performance, said Dr. Páez.
However, the difference between mild and moderate Alzheimer’s disease did not hold up in post hoc analyses that included additional baseline characteristics, including amyloid and APOE e4 status.
“We observed that both mild and moderate subjects performed better than placebo even in the two coprimary endpoints,” Dr. Páez said. “It suggested that the differences between mild and moderate patients was not so apparent.”
The study’s key secondary outcomes included scores on the Clinical Dementia Rating Sum of Boxes (CDR-sb) and the Alzheimer’s Disease Cooperative Study–Clinical Global Impression of Change (ADCS-CGIC) scales. Treated patients scored better than the placebo group on both the CDR-sb (71% less decline, P = .002) and the ADCS-CGIC (100% less decline, P < .0001) scales.
For disease biomarkers in the moderate Alzheimer’s disease study population, levels of CSF Abeta42 and tau protein remained stable in the treated patients. In the placebo group, Abeta42 was decreased and tau protein increased. Dr. Páez explained that, if amyloid in the brain comes from the CSF, this process may take some time.
The findings suggest that more than one mechanism may be involved in the plasma exchange approach, such as changes in oxidation status and inflammatory mediators, the investigators noted.
Safety profile
About 28% of the participants dropped out of the study, which the researchers note is a rate similar to that reported in studies of solanezumab and other treatments in patients with Alzheimer’s disease. “The high percentage (72%) of patients who completed the study further supports that this procedure is feasible in mild to moderate Alzheimer’s disease,” the investigators wrote.
Overall, adverse events were similar to the known safety profile of plasma exchange procedures for other indications. The two most common adverse events were catheter local reactions and hypotension.
Almost 90% of the apheresis procedures were “uneventful,” the researchers reported. Two patients (0.6%) died during the study, which is similar to the low mortality rates reported elsewhere.
However, the investigators stressed that, because many patients with Alzheimer’s disease are in fragile health, plasma exchange treatments should be undertaken with caution, because of its invasive nature.
Dr. Páez noted that a possible limitation of this treatment approach is the availability of plasma for manufacturing plasma products. In the future, this plasma exchange approach might be combined with current and future Alzheimer’s disease therapies.
They are currently in discussions with the American Society for Apheresis, which develops guidelines for plasma exchange. After additional research, the investigators hope to eventually receive Food and Drug Administration approval of plasma exchange with albumin replacement as a treatment for Alzheimer’s disease.