Safety and efficacy of long-term gantenerumab treatment in dominantly inherited Alzheimer's disease: an open label extension of the phase 2/3 multicentre, randomised, double-blind, placebo-controlled platform DIAN-TU Trial.

Background: Amyloid-plaque removal by monoclonal antibody therapies slows clinical progression in symptomatic Alzheimer's disease; however, the potential for delaying the onset of clinical symptoms in asymptomatic people is unknown. The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) is an ongoing platform trial assessing the safety and efficacy of multiple investigational products in participants with dominantly inherited Alzheimer's disease (DIAD) caused by mutations. On the basis of findings of amyloid removal and downstream biological effects from the gantenerumab arm of the platform trial, we continued a 3-year open-label extension (OLE) study to assess the safety and efficacy of long-term treatment with high doses of gantenerumab. Methods: The randomised, placebo-controlled, double-blind, phase 2/3 multi-arm trial (DIAN-TU-001) assessed solanezumab or gantenerumab versus placebo in participants who were between 15 years before to 10 years after their estimated years to symptom onset and had a Clinical Dementia Rating (CDR) global score of 0 (cognitively normal) to 1 (mild dementia). This study was followed by an OLE study of gantenerumab treatment, conducted at 18 study sites in Australia, Canada, France, Ireland, Puerto Rico, Spain, the UK, and USA. For inclusion in the OLE, participants at risk for DIAD had participated in the double-blind period of DIAN-TU-001 and were required to know their mutation status. We investigated increasing doses of gantenerumab up to 1500 mg subcutaneous every 2 weeks. Due to the lack of a regulatory path for gantenerumab, the study was stopped early after a pre-specified interim analysis (when most participants had completed 2 years of treatment) of the clinical measure CDR-SB. The primary outcome for the final analysis was the amyloid plaque measure PiB-PET SUVR at 3 years, assessed in the modified intention to treat population (defined as participants who received any gantenerumab treatment post-OLE baseline, had at least one PiB-PET SUVR assessment prior to gantenerumab treatment, and a post-baseline assessment). All participants who received at least one dose of study drug in the OLE were included in the safety analysis. DIAN-TU-001 (NCT01760005) and the OLE (NCT06424236) are registered with clinicaltrials.gov. Findings: Of 74 participants who were recruited into the OLE study between June 3, 2020 and April 22, 2021, 73 were enrolled and received gantenerumab treatment. 47 (64%) stopped dosing due to early termination of the study by the sponsor, and 13 (18%) prematurely discontinued the study for other reasons. The mITT population for the primary analysis comprised 55 participants. At the interim analysis, the hazard ratio for clinical decline of CDR-SB in asymptomatic mutation carriers was 0.79 (n=53, 95% CI 0.47 to 1.32) for participants who were treated with gantenerumab in either the double-blind or OLE period (Any Gant), and 0.53 (n=22, 0.27 to 1.03) for participants who were treated with gantenerumab the longest (Longest Gant). At the final analysis, the adjusted mean change from OLE baseline to year 3 in PiB-PET SUVR was -0.71 SUVR (95% CI -0.88 to -0.53, p<0.0001). Amyloid-related imaging abnormalities occurred in 53% (39/73) of participants: 47% (34/73) with microhaemorrhages, 30% (22/73) with oedema, and 6% (5/73) were associated with symptoms. No treatment-associated macrohaemorrhages or deaths occurred. Interpretation: Partial or short-term amyloid removal did not show significant clinical effects. However, long-term full amyloid removal potentially delayed symptom onset and dementia progression. Conclusions are limited due to the OLE design and use of external controls and need to be confirmed in long term trials. Funding: National Institutes on Aging, Alzheimer's Association, GHR, F. Hoffmann-La Roche, Ltd/Genentech.