Gantenerumab Fails to Slow Clinical Decline in Early AD Phase 3 Trials

Although gantenerumab improved amyloid plaque and tau 181 in patients with early Alzheimer disease (AD), it was not associated with slower clinical decline, according to study findings published in The New England Journal of Medicine.

Gantenerumab, a subcutaneously administered anti-amyloid IgG1 monoclonal antibody, removes amyloid plaques via microglia-mediated phagocytosis, consequently improving AD biomarkers and slowing down neurodegenerative processes. However, incomplete removal of amyloid plaques has been shown to have little to no clinical benefit.

An international team of researchers conducted 2 phase 3 clinical trials (GRADUATE I and II; ClinicalTrials.gov Identifier: NCT03444870 and NCT03443973, respectively) to evaluate the safety and efficacy of gantenerumab in delaying cognitive and functional decline related to AD.

The researchers enrolled 985 adults in the GRADUATE I trial and 980 adults in the GRADUATE II trial across 288 sites in 30 countries on 5 continents.

Eligible participants were between the ages of 50 and 90 years with mild cognitive impairment (MCI) or mild AD-related dementia. Evidence of amyloid plaques per positron-emission tomography (PET) scans or cerebrospinal fluid (CSF) analysis was required for enrollment in these trials.

The researchers randomly assigned participants to either receive gantenerumab or the placebo in each trial. Over a period of 36 weeks, the dose of gantenerumab was gradually increased from an initial dose of 120 mg every 4 weeks until a target level of 510 mg administered every 2 weeks was reached, regardless of apolipoprotein E (APOE)ε4 genotype.

The researchers analyzed the change in score at week 116 on the Clinical Dementia Rating (CDR) scale-Sum of Boxes compared to baseline measurements to determine gantenerumab efficacy, with higher scores reflective of worse cognitive impairment.

In the GRADUATE I trial, participants taking gantenerumab demonstrated a change from baseline CDR score of 3.35 compared to 3.65 in the placebo group (difference, -0.31; 95% CI, -0.66 to 0.05; P =.10). Similarly, participants taking gantenerumab demonstrated a change from baseline CDR score of 2.82 compared to 3.01 in the placebo group (difference, -0.19; 95% CI, -0.55 to 0.17; P =.30).

While the primary outcome measure did not show significant differences between the groups to confirm gantenerumab efficacy, participants taking gantenerumab demonstrated significantly less amyloid plaque burden on PET scans (-66.44 centiloids in GRADUATE I and -56.46 centiloids in GRADUATE II). Not only did gantenerumab reduce amyloid plaque presence in the brain, but it also reduced levels of phosphorylated tau 181 in the CSF and elevated levels of amyloid-beta (Aβ)-42 in the CSF compared to individuals receiving the placebo.

Approximately 28% of participants in GRADUATE I and 26.8% in GRADUATE II achieved amyloid-negative status after taking gantenerumab. A post-hoc subgroup analysis was performed to determine clinical response in the individuals who achieved amyloid-negative status on gantenerumab; however, no definitive conclusions were made based on the findings.

More serious adverse events (AEs) occurred in the pooled placebo group (16.5%) between the 2 trials compared to the pooled gantenerumab group (13.6%). Discontinuation of the trial due to AEs occurred in 9.1% of pooled participants in the gantenerumab group compared to 1.8% in the pooled placebo group. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in 24.9% of all participants taking gantenerumab with 5% of those experiencing symptoms due to ARIA-E, most commonly headache and dizziness.

“Among persons with early Alzheimer’s disease, the use of gantenerumab led to a lower amyloid plaque burden than placebo at 116 weeks but was not associated with slower clinical decline,” the researchers wrote.

They concluded, “The results of the GRADUATE I and II trials of gantenerumab, taken together with results of trials of other anti-Aβ monoclonal antibodies, suggest the hypothesis that rapid plaque reduction, probably to a level below the threshold of detection, may be necessary to show clinical efficacy within the time frame of 18 to 27 months. However, the current trials did not assess this hypothesis.”

Study limitations included lack of racial diversity in the trial population from the trial sites in the US, the protocol variations of these 2 trials compared to protocols of earlier trials testing anti-amyloid monoclonal antibodies.

Disclosures: Several study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see original source for full list of disclosures.