WASHINGTON, DC—Gantenerumab, a human antibody with high affinity to aggregated amyloid, was associated with dose-dependent reductions in brain amyloid and CSF tau in patients with prodromal Alzheimer’s disease, compared with placebo, according to phase III trial data presented at the 2015 Alzheimer’s Association International Conference. The drug was not, however, associated with significant differences in clinical end points, though researchers found signs of efficacy in patients with a faster rate of disease progression.
“This is the first study showing clear changes on both standard biomarkers [ie, amyloid-PET and CSF tau] in people with very early Alzheimer’s [disease],” said Philip Scheltens, MD, PhD, Professor of Cognitive Neurology and Director of the Alzheimer’s Center at the VU University Medical Center in Amsterdam. “These findings are consistent with brain amyloid clearance and an effect on downstream markers of neurodegeneration. They also suggest that the gantenerumab dose in the phase III SCarlet RoAD trial likely was too low.”
Philip Scheltens, MD, PhD
The findings, considered with emerging data from the PRIME study—a phase I trial of another antiamyloid antibody, aducanumab, that showed dose-dependent reductions in amyloid and slowing of cognitive decline—suggest that higher doses of gantenerumab may be needed to provide clinical benefit, said Robert Lasser, MD, Group Medical Director, Neurodegenerative Disorders, for Roche in Basel, Switzerland. “The phase III program of gantenerumab will continue, incorporating higher doses as we move forward,” he said.
A Trial in Prodromal Alzheimer’s Disease
SCarlet RoAd was a two-year double-blind study that used the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) as the primary end point. More than 3,000 patients were screened for prodromal Alzheimer’s disease, and 797 patients were selected for the study. Patients were between ages 50 and 85 with Mini-Mental State Examination (MMSE) scores of at least 24 and CDR-Global scores of 0.5. Participants also had evidence of amyloid pathology in CSF.
Patients were randomized to placebo or to 105-mg or 225-mg doses of gantenerumab administered every four weeks by subcutaneous injection. Patients were not permitted to use cholinesterase inhibitors or memantine during the study. Only patients with zero or one APOE ε4 alleles could receive the 225-mg dose of gantenerumab.
Exploratory Analysis
Researchers stopped the trial in December 2014 following a preplanned futility analysis using data for the 312 patients who had completed two years in the study by October 2014. Investigators found no significant differences in the CDR-SB, or on MMSE, Alzheimer’s Disease Assessment Scale–cognitive subscale, and the Functional Assessment Questionnaire.
Despite trial screening, only a subset of participants experienced disease progression at the predicted rate. A large portion progressed slowly, and as much as 30% of subjects showed little or no decline over two years. When researchers applied an algorithm by Delor et al to predict fast disease progressers and examined results for this subgroup, they found signs of efficacy. “For fast progressers …. you can appreciate how much less decline is present among subjects with the highest concentrations of gantenerumab, compared to placebo,” Dr. Lasser said.
Biomarker End Points
Investigators measured amyloid-PET in a substudy of 114 patients and found a dose-dependent lowering of amyloid plaques, mainly in the higher dose of 225 mg. “These are small numbers, but the results are statistically significant,” Dr. Scheltens said.
The mean change in amyloid-PET from baseline at Week 100 was –1.11% for placebo, 0.19% for 105 mg of gantenerumab, and –5.37% for 225 mg of gantenerumab.When researchers compared measures of tau in CSF at baseline and after two years, they found a dose-dependent reduction in tau. For phosphorylated tau, the mean change from baseline at week 104 was 2.62% for placebo, –4.85% for the 105-mg dose of gantenerumab, and –7.52% for the 225-mg dose of gantenerumab. For total tau, the mean change was 3.11% for placebo, –1.45% for the 105-mg dose of gantenerumab, and –2.94% for the 225-mg dose of gantenerumab.
Monitoring ARIA
Gantenerumab was safe and well tolerated, and amyloid-related imaging abnormalities (ARIA) and injection-site redness were the most common adverse events, said Dr. Scheltens. The higher incidence of ARIA in the active treatment groups was expected and is a direct result of the intervention, he said.
“Ten years of research have increased our comfort in predicting ARIA by medication dose, time since initiation, and genetic status. With no major long-term consequences of ARIA to date, and the ease of early identification and assessment by MRI … these events can be effectively managed,” said Dr. Lasser. ARIA were generally asymptomatic in roughly 85% of the cases and resolved with dosage reduction. When ARIA was symptomatic, patients reported nonspecific symptoms such as headache or dizziness.