Pharmacodynamic 3-year data from open-label extension studies of gantenerumab have shown that approximately 80% of participants have amyloid levels reduced to a point considered amyloid negative. In addition, approximately half of participants have amyloid levels that are as low as that seen in healthy individuals. These results were reported at the 12th annual Clinical Trials on Alzheimer’s Disease Conference in San Diego, December 4-7, 2019.
The dose of gantenerumab used in the open-label extension studies is the dose being used in the ongoing GRADUATE phase 3 clinical trials (NCT03444870 and NCT03443973). In these trials a single dose of gantenerumab vs placebo is being investigated in people with early Alzheimer’s disease (AD) over a 24-month period. For these studies, early AD is defined as mild cognitive impairment (MCI) to mild AD dementia confirmed with the presence of amyloid biomarkers in cerebrospinal fluid (CSF) or on amyloid-PET scan.
The primary measure for the study is change in the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB). In addition, the Free and Cued Selective Recall Test (FCSRT), which has been shown to predict whether or not people will progress from MCI to AD, is being used as a secondary measure and to rule out confounding results from people with MCI who might not progress to having AD dementia over the course of the study. Other cognitive measures, CSF levels of amyloid and tau, and brain MRI and amyloid-PET studies are among the other secondary outcome measures.
The length of the GRADUATE trials is designed to give participants a long enough exposure to gantenerumab, with the hope of increasing chances of seeing statistically significant and reproducible clinical results. The sample size for the 2 trials has also recently been increased from over 1,500 participants to over 2,000 participants in as part of a commitment to maximize chances of seeing a robust and reproducible result.
Gantenerumab is also being studied as a potential treatment for familial AD in the DIAN-TU trial (NCT01760005). The final patient visit has occurred in that trial, with top-line results expected in 2020.
Gantenerumab binds to fibrillar forms of amyloid found in amyloid plaques in the brain of people with AD. Previous trials have shown that gantenerumab engages fibrillar amyloid in the brain and that it can be administered safely and be well tolerated by people with early AD.
“These findings show continued reduction in beta-amyloid in the brain from the initiation of the open label extension over the ensuing 3 years, continuing toward levels similar to what would be expected in cognitively normal people,” said Geoff Kerchner, global development leader for gantenerumab at Roche. “The clinical significance of gantenerumab’s effect is being investigated in the 2 large, ongoing phase 3 studies, GRADUATE 1 and 2.”