In the phase 2/3 DIAN-TU-001 study (NCT01760005), treatment with the investigational medicine gantenerumab (Genentech, San Francisco, CA) did not significantly slow the rate of cognitive decline in individuals with an early-onset, inherited form of Alzheimer disease (AD). This form of AD, known as autosomal dominant AD (ADAD), accounts for less than 1% of all cases of the disease.. Cognitive decline was measured with the novel DIAN Multivariate Cognitive Endpoint. Gantenerumab's safety profile in DIAN-TU-001 was consistent with that from other clinical trials of the investigational medicine and no new safety issues were identified.
“We are very grateful to all those involved in this study and hope the data can further contribute to the science and collective understanding of this complex disease,” said Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development. “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. Given its experimental nature, we are unable to draw firm conclusions about the impact of gantenerumab in autosomal dominant AD. This outcome does not reduce our confidence in the ongoing phase 3 GRADUATE clinical program.”
Gantenerumab, a late-stage investigational medicine, continues to be studied in 2 large global phase 3 studies (GRADUATE 1 and 2 [NCT03444870 and NCT03443973]) in the broader population of individuals with AD that is not directly caused by gene mutations (sporadic AD). Every participant with ADAD who received gantenerumab in DIAN-TU-001 started on a lower dose and only started titrating to a fivefold higher target dose approximately halfway through the trial, prompted by learnings from other studies of gantenerumab. The GRADUATE studies have been designed from the outset to maximize exposure to gantenerumab, bringing all patients to target dose with minimal or no dose interruption within the study period.
Genentech’s development pipeline for potential treatments for AD spans investigational medicines for different targets, types and stages of AD. In addition to the gantenerumab program, there is an evaluation for semorinemab in a phase 2 study (NCT03828747) in sporadic AD. Crenezumab also continues to be studied in the Alzheimer Prevention Initiative phase 2 trial in ADAD (NCT01998841).
Divakar Mithal, MD, PhD, and Tracy Gertler, MD, PhD
James Geyer, MD, and Paul Cox