Donanemab in Early Symptomatic Alzheimer Disease
Author:
Sims John R.1, Zimmer Jennifer A.1, Evans Cynthia D.1, Lu Ming1, Ardayfio Paul1, Sparks JonDavid1, Wessels Alette M.1, Shcherbinin Sergey1, Wang Hong1, Monkul Nery Emel Serap1, Collins Emily C.1, Solomon Paul2, Salloway Stephen34, Apostolova Liana G.5, Hansson Oskar6, Ritchie Craig7, Brooks Dawn A.1, Mintun Mark1, Skovronsky Daniel M.1, Abreu Rafael8, Agarwal Pinky8, Aggarwal Puja8, Agronin Marc8, Allen Alison8, Altamirano Dario8, Alva Gustavo8, Andersen James8, Anderson Allan8, Anderson Donald8, Arnold Jennifer8, Asada Takashi8, Aso Yasuhiro8, Atit Vikram8, Ayala Ricardo8, Badruddoja Michael8, Badzio-jagiello Hanna8, Bajacek Michal8, Barton David8, Bear David8, Benjamin Sabrina8, Bergeron Richard8, Bhatia Perminder8, Black Sandra8, Block Allan8, Bolouri Mohammad8, Bond Wendy8, Bouthillier Jean8, Brangman Sharon8, Brew Bruce8, Brisbin Sarah8, Brisken Toby8, Brodtmann Amy8, Brody Mark8, Brosch Jared8, Brown Celia8, Brownstone Paul8, Bukowczan Sylwia8, Burns Jeffrey8, Cabrera Alicia8, Capote Horace8, Carrasco Angel8, Cevallos Yepez Jose8, Chavez Eric8, Chertkow Howard8, Chyrchel-paszkiewicz Urszula8, Ciabarra Anthony8, Clemmons Edward8, Cohen Daniel8, Cohen Robert8, Cohen Ian8, Concha Mauricio8, Costell Brian8, Crimmins Denis8, Cruz-pagan Yvette8, Cueli Adolfo8, Cupelo Robert8, Czarnecki Maciej8, Darby David8, Dautzenberg P.l.j.8, De Deyn Peter8, De La Gandara Jose8, Deck Kenneth8, Dibenedetto David8, Dibuono Mark8, Dinnerstein Eric8, Dirican Ahmet8, Dixit Shanker8, Dobryniewski Jacek8, Drake Ryan8, Drysdale Peter8, Duara Ranjan8, Duffy John8, Ellenbogen Aaron8, Faradji Victor8, Feinberg Marc8, Feldman Robert8, Fishman Simon8, Flitman Stephen8, Forchetti Concetta8, Fraga Ivonne8, Frank Andrew8, Frishberg Benjamin8, Fujigasaki Hiroto8, Fukase Hiroyuki8, Fumero Ileana8, Furihata Kenichi8, Galloway Christopher8, Gandhi Rekha8, George Kristi8, Germain Marcel8, Gitelman Darren8, Goetsch Nicholas8, Goldfarb Danielle8, Goldstein Mark8, Goldstick Lawrence8, Gonzalez Rojas Yaneicy8, Goodman Ira8, Greeley David8, Griffin Carl8, Grigsby Eric8, Grosz Daniel8, Hafner Karl8, Hart David8, Henein Sam8, Herskowitz Brad8, Higashi Shinji8, Higashi Yasuto8, Ho Gilbert8, Hodgson Jonathan8, Hohenberg Mark8, Hollenbeck Larry8, Holub Richard8, Hori Tomokatsu8, Hort Jakub8, Ilkowski Jan8, Ingram K. Jennifer8, Isaac Mitchell8, Ishikawa Mitsunori8, Janu Lubos8, Johnston Mark8, Julio William8, Justiz William8, Kaga Tomotsugu8, Kakigi Tatsuya8, Kalafer Marvin8, Kamijo Mikiko8, Kaplan Jeffrey8, Karathanos Michael8, Katayama Sadao8, Kaul Siddharth8, Keegan Andrew8, Kerwin Diana8, Khan Uzma8, Khan Arifulla8, Kimura Noriyuki8, Kirk Gregory8, Klodowska Gabriela8, Kowa Hisatomo8, Kutz Christen8, Kwentus Joseph8, Lai Rosalyn8, Lall Ayesha8, Lawrence Mary8, Lee Elly8, Leon Ramon8, Linker Gary8, Lisewski Pawel8, Liss Jonathan8, Liu Collins8, Losk Scott8, Lukaszyk Ewelina8, Lynch Jennifer8, Macfarlane Stephen8, Macsweeney Josephine8, Mannering Nicholas8, Markovic Oto8, Marks Donald8, Masdeu Joseph8, Matsui Yutaka8, Matsuishi Kunitaka8, Mcallister Peter8, Mcconnehey Brock8, Mcelveen Alvin8, Mcgill Lora8, Mecca Adam8, Mega Michael8, Mensah Jason8, Mickielewicz Anatol8, Minaeian Artin8, Mocherla Bharat8, Murphy Cynthia8, Murphy Paul8, Nagashima Hirotaka8, Nair Anil8, Nair Malini8, Nardandrea John8, Nash Marshall8, Nasreddine Ziad8, Nishida Yoshihiko8, Norton Jeffrey8, Nunez Lazaro8, Ochiai Jun8, Ohkubo Takuya8, Okamura Yasuyuki8, Okorie Eugene8, Olivera Esteban8, O'mahony John8, Omidvar Omid8, Ortiz-Cruz Desiree8, Osowa Alexander8, Papka Michelle8, Parker Alicia8, Patel Paayal8, Patel Ashok8, Patel Meenakshi8, Patry Claude8, Peckham Elizabeth8, Pfeffer Michael8, Pietras Alison8, Plopper Michael8, Porsteinsson Anton8, Poulin Robitaille Raphael8, Prins Niels8, Puente Orlando8, Ratajczak Marcin8, Rhee Margaret8, Ritter Angela8, Rodriguez Ramon8, Rodriguez Ables Lilia8, Rojas Julio8, Ross Jeffrey8, Royer Paule8, Rubin Jay8, Russell David8, Rutgers Sterre Malou8, Rutrick Stephanie8, Sadowski Martin8, Safirstein Beth8, Sagisaka Takafumi8, Scharre Douglas8, Schneider Lon8, Schreiber Curtis8, Schrift Michael8, Schulz Paul8, Schwartz Harvey8, Schwartzbard Julie8, Scott John8, Selem Lissette8, Sethi Pramod8, Sha Sharon8, Sharlin Kenneth8, Sharma Sanjiv8, Shiovitz Thomas8, Shiwach Rajinder8, Sladek Martin8, Sloan Bart8, Smith Amanda8, Solomon Paul8, Sorial Ehab8, Sosa Evelio8, Stedman Mary8, Steen Susan8, Stein Lee8, Stolyar Arkadiy8, Stoukides John8, Sudoh Shinji8, Sutton James8, Syed Junaid8, Szigeti Kinga8, Tachibana Hisatsugu8, Takahashi Yuichi8, Tateno Amane8, Taylor James Dale8, Taylor Kelly8, Tcheremissine Oleg8, Thebaud Adly8, Thein Stephen8, Thurman Louise8, Toenjes Steven8, Toji Hiromasa8, Toma Misaki8, Tran Duc8, Trueba Pilar8, Tsujimoto Masashi8, Turner Raymond8, Uchiyama Akiyoshi8, Ussorowska Dorota8, Vaishnavi Sanjeev8, Valor Elena8, Vandersluis Joel8, Vasquez Alberto8, Velez Juan8, Verghese Cherian8, Vodickova-borzova Klaudia8, Watson David8, Weidman David8, Weisman David8, White Alexander8, Willingham Katherine8, Winkel Izabela8, Winner Paul8, Winston Jaron8, Wolff Adam8, Yagi Hideo8, Yamamoto Hideki8, Yathiraj Sanjay8, Yoshiyama Yasumasa8, Zboch Marzena8,
Affiliation:
1. Eli Lilly and Company, Indianapolis, Indiana 2. Boston Center for Memory and Boston University Alzheimer’s Disease Center, Boston, Massachusetts 3. Department of Neurology and Department of Psychiatry, Alpert Medical School of Brown University, Providence, Rhode Island 4. Butler Hospital, Providence, Rhode Island 5. Department of Neurology, Indiana University School of Medicine, Indianapolis 6. Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden; Memory Clinic, Skåne University Hospital, Lund, Sweden 7. Scottish Brain Sciences, Edinburgh, United Kingdom 8. for the TRAILBLAZER-ALZ 2 Investigators
Abstract
ImportanceThere are limited efficacious treatments for Alzheimer disease.ObjectiveTo assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque.Design, Setting, and ParticipantsMulticenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023).InterventionsParticipants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met.Main Outcomes and MeasuresThe primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes.ResultsAmong 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was −6.02 (95% CI, −7.01 to −5.03) in the donanemab group and −9.27 (95% CI, −10.23 to −8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P < .001) in the low/medium tau population and −10.2 (95% CI, −11.22 to −9.16) with donanemab and −13.1 (95% CI, −14.10 to −12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P < .001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, −0.67 [95% CI, −0.95 to −0.40]; P < .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, −0.7 [95% CI, −0.95 to −0.45]; P < .001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related.Conclusions and RelevanceAmong participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population.Trial RegistrationClinicalTrials.gov Identifier: NCT04437511
Publisher
American Medical Association (AMA)
Cited by
185 articles.
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