After years of unsuccessful trials with monoclonal antibodies directed against specific forms of beta-amyloid, a promising candidate for the treatment of Alzheimer’s dementia now appears to be available for the first time – at least for early forms of the disease. At the American Academy of Neurology Congress in Washington, the results of the PRIME study were discussed again and broken down by ApoE4 status and disease stage. In diagnostics, skin tests could be available in the future.
An epidemiological study at the start of the congress gave an impressive picture of how significant neurological conditions are for disease statistics worldwide. Using data from 1990 to 2013, the authors concluded that the number of deaths attributable to neurological diseases has increased by 50% since 1990. In 2013, 6.4 million deaths were caused by strokes and two million other neurological conditions – including (Alzheimer’s) dementia as the most dominant representative, which accounted for 85% of deaths. Measured by Disability-Adjusted Life Years (DALY), which combines both mortality and morbidity into one number, neurological diseases still account for 8% of the global burden of disease. The authors therefore draw a rather pessimistic conclusion: even if the number of deaths from brain strokes should decrease – due to the increasing aging of the population, mortality from neurological diseases will continue to increase drastically.
It would therefore be all the more important to have instruments at hand that could effectively control precisely such dreaded diseases as Alzheimer’s dementia. Of course, this is still a long way off. However, a new disease-modifying agent, aducanumab (BIIB037), is currently being investigated in a Phase Ib trial for Alzheimer’s dementia. This is a human monoclonal antibody selective for aggregated forms of beta-amyloid peptide. The study aims to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of the compound in patients with prodromal or mild Alzheimer’s dementia.
An interim analysis was presented at the Congress. Results were analyzed separately by disease stage and ApoE4 status. ApoE4 is an allele that individuals who develop Alzheimer’s disease are more likely to have than those without the condition. It is thus a risk factor gene that increases the probability of developing Alzheimer’s dementia – but the exact pathophysiology is not (yet) known.
PRIME: Structure
The mulicenter randomized controlled trial is called PRIME. Patients enrolled in the study were aged 50 to 90 years, had a florbetapir PET scan positive for amyloid (18F-AV-45), and met clinical criteria for prodromal or mild Alzheimer’s disease. By detecting the amyloids, they wanted to make sure that no patients were included who were not suitable for the study. According to estimates, in some previous studies with monoclonal antibodies, up to 30% of patients had too low an amyloid load to be able to derive any significant effects at all.
Participants received aducanumab (intravenous) or placebo once a month for a total of 52 weeks during the double-blind, placebo-controlled phase. The interim results presented are for data from week 26, and the patients studied had already undergone the controls that were in place at that time. The design included seven treatment arms with graduated dose increases and was stratified by ApoE4 status (carrier/noncarrier).
Side effects depending on gene status and dose
AD in 59% of the 165 evaluable participants was classified as mild, and 41% were in the prodromal phase. 65% carried the ApoE4 allele, 35% did not. The most common safety-related adverse events, based on MRI examination, were amyloid-related imaging abnormalities, “amyloid-related imaging abnormalities” (ARIA) such as ARIA edema, microhemorrhage, or hemochromatosis. The study showed that these side effects were dependent on both the aducanumab dose used and the ApoE4 status. First, the results for ApoE4 carriers:
Group 1: 40 subjects received placebo. 8% of them suffered an ARIA.
Group 2: 31 subjects received 1 mg/kg aducanumab. 11% of them suffered an ARIA.
Group 3: 33 subjects received 3 mg/kg aducanumab. 14% of them suffered an ARIA.
Group 4: 30 subjects received 6 mg/kg aducanumab. 43% of them suffered an ARIA.
Group 5: 32 subjects received 10 mg/kg aducanumab. 65% of them suffered an ARIA.
So as the dose increases, so do the side effects. In subjects with AD but without the ApoE4 allele, ARIA analogous to dose increase occurred in 8%, 18%, 11%, and 17% of patients, respectively. For placebo, the rate was 0%. ApoE4 carriers are thus more affected by side effects than patients without this allele. Overall, the rate of ARIA is relatively high – a relevant problem that still needs to be addressed. One thing is clear: you must not increase the dose too much.
Another finding from the study: the time- and therapy-associated reduction of beta-amyloid plaques in the brain (recognizable by the SUVR reduction, “standardized uptake value ratio”) was comparably strong across both gene status groups at the doses tested. Similarly, there were no differences between patients with prodromal or mild AD.
The results of the PRIME study had already attracted a lot of attention at the International Alzheimer’s and Parkinson’s Conference in Nice at the end of March 2015. It had been shown that aducanumab produced significant changes in SUVR in six brain regions at 26 weeks from the 3 mg/kg dose and that the reductions continued to increase until week 52. They were all dose-dependent. There were also significant improvements in the Mini-Mental State and Clinical Dementia ratings compared with placebo (the highest dosage was most effective in each case). Nevertheless, various experts at the congress pointed out that euphoria would be premature and that it would be necessary to wait for further phases in any case, since many active substances often disappoint later after initially good results.
Skin tests to improve Alzheimer’s diagnosis?
Also interesting was the presentation of a new method for Alzheimer’s diagnostics: researchers from Mexico were able to show that skin biopsy samples from subjects with Alzheimer’s dementia have significantly higher levels of tau protein (p-Tau) than the skin biopsies of healthy subjects or those with non-degenerative dementia. The initial hypothesis was that the brain and skin have the same embryonic origin and therefore the abnormal protein deposits must be found in both organs. Evidence for the assumption was provided by retroauricular skin biopsy specimens from a total of 65 subjects: 20 with AD, 16 with PD, 17 with non-neurodegenerative dementia, and 12 healthy matched controls).
The immunohistochemical test could be used as a complementary diagnostic tool in the future. Supplied routinely by standard laboratories, this would facilitate differential diagnosis. It would be a considerable advance to be able to detect the aggregated tau fibrils characteristic of Alzheimer’s disease not only post mortem in brain tissue, but also in the skin of living patients. Now the goal is to test the test in larger groups of people.
Source: Amercian Academy of Neurology Annual Meeting, April 18-25, 2015, Washington, USA.
InFo NEUROLOGY & PSYCHIATRY 2015; 13(3): 22-24.
