First study of Alzheimer’s disease prevention with amyloid-targeting drugs gantenerumab or solanezumab

A global treatment and prevention study with gantenerumab or solanezumab in patients with dominantly inherited Alzheimer’s disease (DIAD) found no changes in cognitive decline, but some clinical improvements in downstream biomarkers. These results were published in Nature Medicine.

A total of 236 people at high risk for DIAD mutations were screened at 25 locations in 7 countries 10-15 years prior to the expected age of Alzheimer’s disease (AD) from 2012 to 2019. Among the mutation carriers (n = 144) 52 received subcutaneous gantenerumab (225 mg every 4 weeks up to 1,200 mg in 2016), 52 received intravenous solanezumab (400 mg every 4 weeks up to 1,600 in 2017), 21 received subcutaneous placebo and 19 intravenous placebo. Participants were assessed for cognitive outcomes every 6 months, a clinical assessment was performed every year, and biomarkers were assessed at baseline and in years 1, 2, and 4.

At randomization, 60% of each active treatment arm and 55% of controls were asymptomatic. During the study, the doses of the active ingredients were increased based on the results of the Phase 2 and 3 studies. The mean duration of treatment was 4.02 (range, 0.90-6.49) years.

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The cohorts of gantenerumab, solanezumab, and combined placebo averaged 46.0 ± 10.8, 42.5 ± 9.5, and 44.2 ± 9.6 years old, 40%, 58%, and 55% were women and ≥ 80% of each cohort were carriers of presenilin-1 (PS1) or

The cognitive progression ratio (CPR) for gantenerumab was 1.063 while the CPR for solanezumab was 1.255, both of which suggest that treatment has no effect on cognition.

Stratified by baseline asymptomatic status, those who were asymptomatic showed no cognitive decline during the study. According to the scores of the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the symptomatic persons decreased from the initial value (3.2 ± 1.9) to the dose escalation (5.9 ± 4.4).

The deposition of amyloid in the brain was lower in gantenerumab recipients compared to placebo in years 2 (4% reduction vs. 5% increase; p <0.001) and 4 (12.7% decrease vs. 11.6% increase; p < 0.001) significantly reduced. For solanezumab, the amyloid disposition was significantly increased in years 2 (93.3% increase vs. 6.7% increase; P <0.001) and 4 (200.5% increase vs. 0% increase; P <0.001).

In year 4, the gantenerumab cohort showed a significantly increased CSF Aβ42 (19.3% increase vs. 23.3% decrease; P <0.001), decreased total tau (15.3% decrease vs. 5, 3% increase; P <0.001) and reduced phospho-tau181 (23.4% decrease vs. 9.4% increase; p <0.001) compared to placebo.

Amyloid-related imaging abnormalities – brain edema – were seen in 19.2% of the gantenerumab, 0% of the solanezumab, and 2.5% of the placebo cohorts. Most of these cases were asymptomatic (8 of 11) and the mean time to resolution was 85.5 ± 54.3 days.

This study may have been limited by the dose escalation over the course of the study.

This study was the first AD prevention study with amyloid-targeting drugs. The study authors concluded that although no cognitive effects were observed, downstream biomarkers were improved in the gantenerumab recipients, which may indicate a long-term benefit in slowing disease progression.

Disclosure: Several authors stated links to industry. For a full list of details, see the original article.

reference

Salloway, M. Farlow, E. McDade, et al. A study of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat. Med. Published online June 21, 2021. doi: 10.1038 / s41591-021-01369-8

This article originally appeared on Psychiatry Advisor