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@ARTICLE{Bateman:277740,
      author       = {Bateman, Randall J and Li, Yan and McDade, Eric M and
                      Llibre-Guerra, Jorge J and Clifford, David B and Atri,
                      Alireza and Mills, Susan L and Santacruz, Anna M and Wang,
                      Guoqiao and Supnet, Charlene and Benzinger, Tammie L S and
                      Gordon, Brian A and Ibanez, Laura and Klein, Gregory and
                      Baudler, Monika and Doody, Rachelle S and Delmar, Paul and
                      Kerchner, Geoffrey A and Bittner, Tobias and Wojtowicz,
                      Jakub and Bonni, Azad and Fontoura, Paulo and Hofmann,
                      Carsten and Kulic, Luka and Hassenstab, Jason and
                      Aschenbrenner, Andrew J and Perrin, Richard J and Cruchaga,
                      Carlos and Renton, Alan E and Xiong, Chengjie and Goate,
                      Alison A and Morris, John C and Holtzman, David M and
                      Snider, B Joy and Mummery, Catherine and Brooks, William S
                      and Wallon, David and Berman, Sarah B and Roberson, Erik and
                      Masters, Colin L and Galasko, Douglas R and Jayadev, Suman
                      and Sanchez-Valle, Rachel and Pariente, Jeremie and
                      Kinsella, Justin and van Dyck, Christopher H and Gauthier,
                      Serge and Hsiung, Ging-Yuek Robin and Masellis, Mario and
                      Dubois, Bruno and Honig, Lawrence S and Jack, Clifford R and
                      Daniels, Alisha and Aguillón, David and Allegri, Ricardo
                      and Chhatwal, Jasmeer and Day, Gregory and Fox, Nick C and
                      Huey, Edward and Ikeuchi, Takeshi and Jucker, Mathias and
                      Lee, Jae-Hong and Levey, Allan I and Levin, Johannes and
                      Lopera, Francisco and Roh, JeeHoon and Rosa-Neto, Pedro and
                      Schofield, Peter R},
      collaboration = {Unit, Dominantly Inherited Alzheimer's Disease-Trials},
      title        = {{S}afety and efficacy of long-term gantenerumab treatment
                      in dominantly inherited {A}lzheimer's disease: an open-label
                      extension of the phase 2/3 multicentre, randomised,
                      double-blind, placebo-controlled platform {DIAN}-{TU}
                      trial.},
      journal      = {The lancet},
      volume       = {24},
      number       = {4},
      issn         = {1474-4422},
      address      = {London},
      publisher    = {Lancet Publ. Group},
      reportid     = {DZNE-2025-00461},
      pages        = {316 - 330},
      year         = {2025},
      abstract     = {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). Based on findings of amyloid removal and downstream
                      biological effects from the gantenerumab group 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.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 and
                      10 years after their estimated years to symptom onset and
                      who 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 the 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 subcutaneous gantenerumab up to 1500 mg
                      every 2 weeks. Due to the lack of a regulatory path for
                      gantenerumab, the study was stopped early after a
                      prespecified interim analysis (when most participants had
                      completed 2 years of treatment) of the clinical measure
                      CDR-Sum of Boxes (CDR-SB). The primary outcome for the final
                      analysis was the amyloid plaque measure 11C-Pittsburgh
                      compound-B positron emission tomography (PiB-PET)
                      standardised uptake value ratio (SUVR [PiB-PET SUVR]) at 3
                      years, assessed in the modified intention-to-treat group
                      (mITT; defined as participants who received any gantenerumab
                      treatment post-OLE baseline, had at least one PiB-PET SUVR
                      assessment before 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.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; 13 people completed 3 years of treatment. The mITT
                      group 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
                      of 73) of participants: $47\%$ (34 of 73) with
                      microhaemorrhages, $30\%$ (22 of 73) with oedema, and $6\%$
                      (five of 73) were associated with superficial siderosis. No
                      treatment-associated macrohaemorrhages or deaths
                      occurred.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. Our conclusions are limited due to the
                      OLE design and use of external controls and need to be
                      confirmed in long-term trials.National Institute on Aging,
                      Alzheimer's Association, GHR Foundation, and F Hoffmann-La
                      Roche/Genentech.},
      keywords     = {Humans / Antibodies, Monoclonal, Humanized: therapeutic use
                      / Antibodies, Monoclonal, Humanized: pharmacology /
                      Antibodies, Monoclonal, Humanized: administration $\&$
                      dosage / Double-Blind Method / Male / Female / Alzheimer
                      Disease: drug therapy / Alzheimer Disease: genetics / Middle
                      Aged / Treatment Outcome / Adult / Aged / Antibodies,
                      Monoclonal, Humanized (NLM Chemicals) / gantenerumab (NLM
                      Chemicals) / solanezumab (NLM Chemicals)},
      cin          = {AG Jucker},
      ddc          = {610},
      cid          = {I:(DE-2719)1210001},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40120616},
      doi          = {10.1016/S1474-4422(25)00024-9},
      url          = {https://pub.dzne.de/record/277740},
}