This announcement is regarding the Knight Family DIAN-TU Open Label Extension (OLE) Study with gantenerumab (made by Roche and Genentech) [Clinicaltrials.gov #NCT01760005].
Based on the results of the completed Roche Phase 3 GRADUATE studies of gantenerumab in sporadic AD in late 2022, it was decided to determine if dominantly inherited Alzheimer’s disease (DIAD) participants in the DIAN-TU-001 OLE study were benefiting from gantenerumab high-dose treatment. The DIAN-TU and Roche performed an interim efficacy analysis of the DIAN-TU-001 OLE to:
- determine if gantenerumab OLE treatment and/or long-term treatment results in clinical benefit and determine the extent of amyloid removal compared to the double-blind period.
- determine the potential effects of gantenerumab on clinical and cognitive measures to support decision-making regarding next steps for the DIAN-TU-001 OLE.
The primary outcome did not show pre-specified threshold changes in outcomes between the gantenerumab treated and controls. One of the subgroups did meet the pre-specified threshold. Based on these findings, and the status of gantenerumab development plan, Roche and the DIAN-TU have decided to discontinue the DIAN-TU-001 gantenerumab OLE. Other measures are being analyzed and will be communicated in scientific meetings and publications.
The Knight Family DIAN-TU and Roche recognize and truly appreciate the commitment of our participants and their families. The DIAN-TU understands the uncertainty and concerns with stopping treatment, and we are actively working to identify treatment continuation and trial options for the DIAN-TU-001 OLE participants with expected announcements in the next few months. A wash-out period after last dose may be necessary prior to starting treatment with another anti-amyloid drug and potentially other AD treatments. Based on observations in other studies, the effect of the drug on brain amyloid removal likely lasts many years after the last dose. In addition, the drug remains in the body (i.e. keeps working) at decreasing concentrations for as long as 6 months after the last dosing, and it takes many years for amyloid deposits in plaques to accumulate in the brain. Thus, a break in treatment between studies should have minimal, if any, effect on amyloid removed from the brain in the DIAN-TU-001 OLE participants treated with gantenerumab.
In June 2020, the Knight Family DIAN-TU, in collaboration with Roche and Genentech, launched an exploratory Open Label Extension (OLE) with gantenerumab [Clinicaltrials.gov #NCT01760005] following the close of the DIAN-TU-001 secondary prevention trial of gantenerumab and solanezumab. The DIAN-TU-001 gantenerumab OLE protocol enrolled eligible individuals who participated in the DIAN-TU-001 double-blind trial of solanezumab or gantenerumab and was designed to provide up to 3 years of treatment with higher doses of gantenerumab. The goals of the DIAN-TU-001 OLE were:
- to allow participants, who have committed 4 to 7 years to the double‐blind treatment period of the study, to continue or begin to receive gantenerumab, which improved some biological markers of their progressive disease;
- to determine if continued treatment with gantenerumab at its target dose can result in complete removal of brain amyloid;
- to investigate which non‐amyloid related downstream biological measures (e.g. tau and neurodegeneration) can be improved or normalized with complete removal of amyloid at different stages of disease; and
- to investigate the relationship of these biological measures with cognitive and clinical findings.
In late 2022, when it was learned that the GRADUATE studies of gantenerumab, in patients with sporadic AD, were negative, it was decided that an interim efficacy analysis of the DIAN-TU-001 OLE should be performed to see if the higher doses of gantenerumab used in the OLE were providing a benefit to patients with DIAD. The primary outcomes for the interim were slowing of clinical and cognitive decline as measured by the Clinical Dementia Rating (CDR) – global score and the CDR Sum of Boxes (CDR-SB) – of participants who were asymptomatic at their baseline visit. Secondary outcomes included amyloid removal and tau accumulation in the brain as measured by Positron Emission Tomography (PET), changes in amyloid and tau protein levels in cerebrospinal fluid (CSF), and other measures of memory and cognition.
DIAN-TU researchers will continue to analyze data according to the DIAN-TU-001 OLE Statistical Analysis Plan to further understand the outcomes of the study. A more detailed presentation of the study results will be presented to stakeholders in the coming months.
We thank the DIAN-TU participants and their families, site investigators and coordinators, Pharma Collaborators, our funders (the NIA/NIH, Alzheimer’s Association, GHR Foundation, and other organizations), regulators, the DIAN-TU Study Team, Washington University Leadership, vendors, and many others for their continued support of the DIAN-TU trials. We remain committed to our participants who have dedicated many years, some more than 10, to the DIAN-TU trials and whose contributions have provided key insights into the progression and treatment of AD, led to the identification of stage dependent changes with amyloid removal, and helped in the development of potential surrogate biomarkers.
The DIAN-TU is informing study participants and applicable health authorities, study ethics committees, and institutional review boards about the decision on the DIAN-TU-001 OLE.
The DIAN-TU-001 OLE is supported by Roche, the Alzheimer’s Association, GHR Foundation, and the Knight Family DIAN-TU. The DIAN-TU-001 trial of solanezumab and gantenerumab was supported by Eli Lilly & Company, Roche, the Alzheimer’s Association, the National Institutes of Health (NIH U01AG042791, PI RJ Bateman; NIH R01AG046179, PI RJ Bateman), GHR Foundation, and FBRI.
| Randall J. Bateman, MD Director, DIAN-TU | David Clifford, MD Medical Director, DIAN-TU | Ali Atri, MD, PhD DIAN-TU-001 OLE Project Arm Leader, DIAN-TU |
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