Crenezumab and Gantenerumab In Phase 3 Trials for Treating Persons with Alzheimer’s Disease

Thursday, July 26, 2018

Crenezumab and Gantenerumab are 2 monoclonal antibodies directed against amyloid-ß (Aß) soluble and oligomeric forms. Crenezumab more specifically targets oligomers, whereas gantenerumab more specifically targets Aß plaque.

 After 69 weeks of treatment, 86% of patients with AD who were treated with intravenous crenezumab had lower cerebrospinal fluid (CSF) levels of Aß oligomers compared to their baseline level prior to treatment. In those treated with subcutaneous crenezumab, 89% had lower CSF Aß levels compared to their pretreatment baseline. The median reduction in CSF Aß for those treated intravenously was 43% (P = .01). For those treated with subcutaneous crenezumab, the median reduction was 48% (P = .001).

 Enrollment has been completed for 2 large phase 3 clinical trials of crenezumab for patients with early (prodromal to mild) AD. Inclusion criteria for enrolled persons are that they are amyloid positive as measured by CSF levels or on amyloid PET imaging. Clinical criteria include neuropsychologic tests for specific memory deficits known to be likely to progress to AD. 

 The Aß plaque target for gantenerumab allows the use of neuroimaging as a measure for the effects of treatment.  To evaluate the effects of higher doses and different up-titration regimens of gantenerumab, earlier studies that had not achieved specific endpoints were converted to open-label extension studies. Data from these open-label studies were used to support the design of 2 ongoing phase 3 clinical trials, which are evaluating the efficacy and safety of higher-dose gantenerumab in patients with early (prodromal and mild) AD. 

 Importantly, when antibodies target Aß plaque, there is a risk of amyloid-related imaging abnormalities (ARIA), and data has been presented showing that the risk of ARIA is relatively low with the use of gantenerumab, and that more than 80% of people in whom ARIA did occur had no or mild clinical symptoms. This allows for safe dosing of gantenerumab in new trials that is 5 times higher than what was used before.

 In addition to monoclonal antibody treatments, Roche is working on development of CSF and serum Aß-42 and phospho-tau as biomarkers on the widely available Elecsys platform. These have been approved in Europe and granted breakthrough designation by the US Food and Drug Administration for study in the US.

 Rachelle Doody, MD, PhD, Global Head of Neurodegeneration at Roche and Genentech stated, “We, at Roche and Genentech develop both diagnostics and medicines. Our goal is to have a set of complete solutions for people who need to be evaluated for cognitive impairments and potential AD—including screening tools to determine if they need to be tested in depth, tools to help their clinician choose the right medication, medical treatment options if they do have AD, and tools to monitor how treatment is working  using easily measured biomarkers.”

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