First Alzheimer Disease Prevention Trial Using Amyloid-Targeting Drugs Gantenerumab or Solanezumab

A global treatment and prevention trial of gantenerumab or solanezumab for patients with dominantly inherited Alzheimer disease (DIAD) found no changes in cognitive decline but some clinical improvements of downstream biomarkers. These findings were published in Nature Medicine.

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

At randomization, 60% of each active treatment arm and 55% of the controls were asymptomatic. During the trial the doses of the active drugs were increased due to results of the phase 2 and 3 trials. The average treatment duration was 4.02 (range, 0.90-6.49) years.

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

The cognitive progression ratio (CPR) for gantenerumab was 1.063, while the CPR for solanezumab was 1.255, both indicating no treatment effect on cognition.

Stratified by asymptomatic status at baseline, those who were asymptomatic did not exhibit a cognitive decline during the study. Symptomatic individuals declined according to Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores from baseline (3.2±1.9) to dose escalation (5.9±4.4).

Brain amyloid deposition was significantly reduced among gantenerumab recipients compared with placebo at years 2 (4% reduction vs 5% increase; P <.001) and 4 (12.7% decrease vs 11.6% increase; P <.001). For solanezumab, amyloid disposition was significantly increased at years 2 (93.3% increase vs 6.7% increase; P <.001) and 4 (200.5% increase vs 0% increase; P <.001).

At year 4, the gantenerumab cohort had significantly increased cerebrospinal fluid (CSF) Aβ₄₂ (19.3% increase vs 23.3% decrease; P <.001), reduced total tau (15.3% decrease vs 5.3% increase; P <.001), and reduced phospho-tau181 (23.4% decrease vs 9.4% increase; P <.001) compared with placebo.

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

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

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

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.

Reference

Salloway S, Farlow M, McDade E, et al. A trial 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