NEW YORK (GenomeWeb) – In another disappointment for Alzheimer's therapeutic research, Roche announced last week that it has discontinued the Phase III Scarlet Road study involving the monoclonal antibody gantenerumab in pre-dementia patients.
However, Roche is planning to continue to investigate the drug in more advanced Alzheimer's patients with mild dementia in another Phase III trial. In that study, researchers will attempt to accurately diagnose the disease and track patients with mild Alzheimer's with the help of cerebral spinal fluid biomarkers.
Roche decided to stop Scarlet Road "based on results of a pre-planned futility analysis and recommendation by the independent Data Monitoring Committee," the company said in a statement.
Currently, other than expressing disappointment with the study results, Roche isn't ready to dissect what occurred or failed to occur in the trial. Roche spokesperson Ulrike Engels-Lange noted that the study wasn't stopped due to safety concerns.
"Scarlet Road was the first Phase III study to test a potential disease-modifying therapy in patients with prodromal Alzheimer's disease," or pre-dementia, Engels-Lange explained. "It is premature to comment until Roche has fully reviewed the data from this study." The company has said it plans to publicly share the data from Scarlet Road after a full analysis.
According to Clinicaltrials.gov, the study aimed to enroll more than 700 patients between 50 and 85 years old and randomize them to receive either gantenerumab or placebo. As part of a substudy, researchers were using PET scans to track whether the amount of beta-amyloid in patients' brains changed over time.
Gantenerumab is an antibody designed to bind to and get rid of beta-amyloid, the peptide that makes up much of the plaque found in the brains of Alzheimer's patients. Roche's development of gantenerumab follows the so-called amyloid hypothesis, which has dominated Alzheimer's research for more than 20 years and asserts that beta-amyloid peptides build up in the brain, form into sticky plaques, kill neurons, and cause dementia.
However, the aggregation of beta-amyloid doesn't always line up with clinical symptoms of Alzheimer's. Studies have shown that amyloid starts to accumulate as many as 15 years before patients start to lose their cognitive faculties. Meanwhile, 33 percent of patients who are cognitively normal are found to have amyloid deposits in their brain at autopsy.
Historically, a definitive diagnosis of Alzheimer's can only come after death, upon analyzing the plaques and tangles in brain tissue. In recent years, however, in an attempt to improve diagnosis of the disease, drugmakers have been testing for beta-amyloid and tau proteins in cerebral spinal fluid and using PET scans to visualize amyloid in living patients.
As such, just the presence or absence amyloid can't be used to diagnose Alzheimer's. In its draft guidance on developing drugs for early-stage Alzheimer's, the US Food and Drug Administration said that it supports using biomarkers to enrich clinical trials with people most likely to progress to overt dementia, but the agency doesn't back these biomarkers as standalone diagnostics for Alzheimer's.
Since Scarlet Road wasn't stopped due to safety issues, Roche said it will investigate the drug in the Phase III Marguerite RoAD trial involving advanced Alzheimer's patients with mild dementia. "A potential treatment effect may be detected in this patient population within the timeframe of the study," Engels-Lange said. "Until Roche fully reviews Scarlet Road study data and understands implications, Marguerite RoAD will continue to enrol patients."
In a 2012 interview with Alzforum.org, Luca Santarelli, head of neuroscience, ophthalmology, and rare diseases at Roche's early pharma R&D division, noted that researchers were using a commercially available research-grade test to assess beta-amyloid in patients' cerebral spinal fluid and cognitive testing to identify the patients with underlying AD pathology in gantenerumab trials.. He added at the time that Roche was “developing a companion diagnostic assay test for future use.”
Roche may still be committed to that plan. The Phase III trial of gantenerumab in 1,000 mild Alzheimer's patients is indeed assessing change in beta-amyloid and tau levels in cerebral spinal fluid as a secondary outcome measure.
Roche wouldn't comment on whether having to discontinue Scarlet Road was a hit against the amyloid hypothesis, a theory that a number of prominent Alzheimer's researchers say needs reconsideration after a number of amyloid-targeting drugs – such as Pfizer/Johnson & Johnson's bapineuzumab and Lilly's solanezumab – have failed to improve cognitive abilities in patients. In the case of solanezumab, Lilly is continuing to pursue development in patients with a very mild form Alzheimer's, a group in which the company believes the drug still holds some promise based on earlier trials. In this study, Lilly is using PET imaging to visualize who has amyloid build up and tracking beta-amyloid levels in cerebral spinal fluid.
Despite the setback with Scarlet Road, Alzheimer's remains a big R&D focus at the company. Roche is developing the anti-amyloid antibody crenezumab and a monoamine oxidase-B inhibitor RG1577 in Phase II trials.
For the monoclonal antibody crenezumab, Roche subsidiary Genentech in 2012 launched a Phase II trial in Medellin, Colombia, where approximately 5,000 residents share a common ancestor and have a high prevalence of mutations in the presenelin 1 gene. Those harboring the dominant gene mutation will start to lose their memory in their mid-40s and their cognitive functions will deteriorate by age 50. Genentech has said that by investigating the drug in a genetically homogeneous group, this will be the "ultimate test" of the amyloid hypothesis.