medwireNews: Gantenerumab has failed to significantly slow cognitive impairment in people with early Alzheimer’s disease (AD) in the phase 3 GRADUATE I and II trials.
Neither study met the primary endpoint of a significantly smaller decline from baseline in the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB) score by week 116 with gantenerumab, an anti-Aβ immunoglobulin G1 antibody, than with placebo, the investigators report in The New England Journal of Medicine.
“The results for secondary clinical outcomes were [also] not supportive of a beneficial clinical effect of the drug,” they add.
Both trials recruited individuals aged 50–90 years with mild cognitive impairment or dementia due to AD, a CDR–Global Score of 0.5 or 1.0, and positron emission tomography (PET) or cerebrospinal fluid (CSF) evidence of amyloid plaque.
Writing in an accompanying comment, Lon Schneider (University of Southern California, Los Angeles, USA) describes the findings as “surprising” given that gantenerumab has an overlapping binding site to that of aducanumab and lecanemab, both of which have already received US FDA approval for the treatment of early AD on the basis that they “markedly reduce amyloid plaque deposition.”
But he highlights that GRADUATE I and II participants had higher CDR-SB scores and amyloid loads at baseline than patients in the other trials, resulting in greater residual plaque at follow-up, which “might have led to differences in the outcomes” across the studies.
In the GRADUATE I trial of 985 patients, the change from baseline in CDR-SB score with gantenerumab titrated over 36 weeks to a target of 510 mg every 2 weeks was a nonsignificant 3.35 versus 3.65 with placebo, and the corresponding nonsignificant score changes for the GRADUATE II study of 980 patients were 2.82 versus 3.01.
Randall Bateman (Washington University School of Medicine, St Louis, Missouri, USA) and co-investigators explain that the hierarchical design of the trial analysis meant that a lack of significant difference in the week 116 CDR-SB scores between the treatment arms precluded significant differences being detected in the three confirmatory secondary measures of cognitive and functional impairment.
However, patients treated with gantenerumab in both the GRADUATE I and II studies did have lower PET amyloid levels at week 116 than their placebo-treated counterparts, with between-group differences of 66.44 and 56.46 centiloids.
And at week 116, 28.0% of GRADUATE I participants given gantenerumab were amyloid-negative (≤24 centiloids) versus 2.4% of controls, with a similar pattern among the GRADUATE II participants, at 26.8% and 0.0%, respectively.
Although there was “no appreciable difference” between the gantenerumab and placebo groups for PET assessment of tau at week 116, CSF testing showed that gantenerumab-treated patients had lower geometric mean levels of total tau, phosphorylated tau 181, and Aβ40 than controls, as well as better outcomes for CSF biomarkers of synaptic integrity and neurodegeneration.
Pooled safety results for the two trials show that one or more adverse events (AEs) occurred in a comparable 90.1% of gantenerumab-treated patients and 87.1% of controls, including serious AEs in 13.6% and 16.5%, respectively. But participants given gantenerumab were more likely than controls to discontinue treatment because of AEs (9.1 vs 1.8%) and this was driven by an increased risk for amyloid-related imaging abnormalities caused by cerebral edema or microhemorrhage (13.5 vs 0.7%), particularly new episodes caused by cerebral microhemorrhages (22.9 vs 12.3%).
“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,” Bateman et al conclude.
“However, the current trials did not assess this hypothesis,” they admit.
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