The Switzerland-based pharmaceutical company Hoffmann-La Roche Ltd has discontinued a phase 3 study of its investigational antiamyloid agent gantenerumab in prodromal Alzheimer's disease (AD).
The decision to halt the study was based on results of a preplanned futility analysis and a recommendation by the independent data monitoring committee, the company said in a press release. The company noted that there were no new safety signals for gantenerumab in the analysis and that the overall safety profile was similar to that seen in the phase 1 trial.
Findings from the phase 3 trial, SCarlet RoAD, which will be shared with the medical community after full review and analysis, will inform future research programs, approaches, and clinical trial design, the statement said.
After consultation with Roche, leaders involved in the DIAN-TU (Dominantly Inherited Alzheimer Network-Trials Unit) trial have decided that the outcome of the SCarlet RoAD futility analysis won't affect that trial, according to Michael Purdy, senior science writer, Washington University School of Medicine, Office of Medical Public Affairs, St. Louis, Missouri. DIAN-TU-001 is investigating gantenerumab and another antiamyloid agent (solanezumab) in volunteers who carry a mutation that causes early AD.
"We are disappointed with these study results because people with early stage Alzheimer's need new medicines that delay disease progression," Sandra Horning, MD, chief medical officer and head of global product development at Roche, said in the release. "This is the first phase 3 trial to evaluate a potential disease-modifying medicine in this early prodromal stage of Alzheimer's disease. We remain committed to investigating new medicines for this devastating illness."
Gantenerumab is a fully human monoclonal antibody designed to decrease levels of β amyloid (Aβ), a protein that accumulates in the brain of people with AD and is hypothesized to play a central role in disease development and progression.
Earlier research had demonstrated that treatment with gantenerumab resulted in a dose-dependent reduction of brain amyloid in patients with mild to moderate AD, although the small trial noted no consistent treatment effects on cognitive measures. That study had data from 16 patients with AD, aged 50 to 90 years, who were included in a positron emission tomographic (PET) substudy of a larger multiple-ascending-dose trial.
The patients were assigned to receive intravenous infusions of gantenerumab (60 mg, n = 6; 200 mg, n = 6) or placebo (n = 4) once every 4 weeks to a total of seven infusions, but because of early termination of dosing in the 200-mg gantenerumab group, not all participants received seven infusions. The study found a mean percentage reduction from baseline in cortical brain amyloid relative to placebo of 15.6% in the 60-mg group and 35.7% in the 200-mg group.
DIAN-TU-001, a placebo-controlled double-blind trial, is investigating the safety, tolerability, and biomarker efficacy of solanezumab and gantenerumab in patients with an autosomal dominant AD mutation. The trial, launched in December 2012, has 15 sites in the United States, Canada, and Puerto Rico and 12 international sites in Australia, France, Italy, the United Kingdom, and Spain.
The primary endpoint is the amount of fibrillary amyloid deposition as measured by PET scans (gantenerumab) and concentrations of Aβ species, specifically different treatment effects on free cerebrospinal fluid (CSF) Aβ42, and free CSF Aβ40 with similar treatment-associated increases in CSF total Aβ42 and Aβ40 (solanezumab), at 2 years.
The trial is sponsored by Washington University School of Medicine. Collaborators include the Alzheimer's Association and Eli Lilly and Company, in addition to Hoffmann-La Roche. Principal investigator is Randall J. Bateman, MD, Charles F. and Joanne Knight Distinguished Professor of Neurology, Washington University School of Medicine.
According to Purdy, gantenerumab will continue to be tested in the DIAN-TU-001 trial because the trial includes a population medically and scientifically different from that of SCarlet RoAD, namely those at genetic risk for early-onset AD vs sporadic late-onset AD. It's a prevention study, and the primary outcome will consider effects on biomarkers before considering the cognitive endpoint phase of the trial.
Experts predict that without an effective treatment, the number of Americans with AD will double by 2050 to more than 10 million, and related healthcare costs could soar to over $1 trillion a year. This is in addition to the caregiver burden, which can take a serious toll on the physical, mental, and financial well-being of family members.
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Cite this: Trial of Antiamyloid Agent in Prodromal Alzheimer's Halted - Medscape - Dec 24, 2014.