Roche's gantenerumab fails Phase II/III trial in rare inherited form of Alzheimer's disease

Roche announced top-line results Monday from the Phase II/III DIAN-TU-001 study showing that its experimental drug gantenerumab did not significantly slow the rate of cognitive decline in patients who have an early-onset, inherited form of Alzheimer's disease, compared with placebo. According to the Swiss drugmaker, the results do not impact its two ongoing Phase III GRADUATE 1 and GRADUATE 2 trials of gantenerumab, an IgG1 monoclonal antibody designed to bind to aggregated forms of beta-amyloid, in patients with the common form of Alzheimer's disease that is not directly caused by gene mutations. 

"Although DIAN-TU didn't reach its primary endpoint, the trial represents the first of its kind and a bold undertaking by all partners involved," commented Levi Garraway, Roche's head of global product development. The study, which was established in 2010 and sponsored by Washington University School of Medicine, tested gantenerumab as well as Eli Lilly's investigational anti-amyloid monoclonal antibody solanezumab, to determine if either could slow the rate of cognitive decline and improve disease-related biomarkers in patients known to have a genetic mutation for inherited Alzheimer's disease. The primary outcome for the study is the DIAN Multivariate Cognitive Endpoint, which Roche said is a novel outcome measure designed to assess cognitive performance in patients with autosomal dominant Alzheimer's disease. 

Separately on Monday, Eli Lilly said that solanezumab had also missed the study's primary endpoint. 

Roche said the trial followed 194 participants for an average of about five years, with 52 patients randomised to receive active gantenerumab. The drugmaker noted that all participants came from families that carry a genetic mutation that causes inherited Alzheimer's disease, with some not yet exhibiting symptoms of the disease at the time of enrollment, as well as some who already had mild symptoms. Aside from the primary endpoint, secondary goals for gantenerumab included cerebral amyloid imaging, as well as various clinical and cognitive changes from baseline versus matching placebo. 

Roche also noted that patients who received gantenerumab in DIAN-TU-001 started on a lower dose and only began titrating to a five-fold higher target dose approximately halfway through the trial, whereas the GRADUATE studies have been designed "from the outset to maximise exposure to gantenerumab, bringing all patients to target dose with minimal or no dose interruption within the study period." 

In 2014, Roche ended the Phase III SCarlet RoAD study of gantenerumab in prodromal Alzheimer's disease based on the results of a pre-planned futility analysis. Last year, the company also halted the late-stage CREAD 1 and CREAD 2 trials of the anti-beta-amyloid therapy crenezumab in patients with early sporadic Alzheimer's disease after a pre-planned interim analysis indicated that the trials were unlikely to meet their primary endpoints. 

In addition to the gantenerumab programme, Roche is testing crenezumab in the Alzheimer's Prevention Initiative Phase II trial in autosomal dominant Alzheimer's disease, while the anti-tau monoclonal antibody semorinemab, also known as RG6100, is being evaluated in Phase II studies in sporadic Alzheimer's disease. 

Meanwhile, Biogen recently indicated that it plans to seek US regulatory approval for its anti-amyloid beta antibody aducanumab, partnered with Eisai, "as soon as possible" after the companies revived the Alzheimer's drug late last year based on a new analysis of two previously-shelved studies. 


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